@article {pmid41449506,
year = {2025},
author = {Shulman, M and Wu, S and Xie, J and Huang, E and Edwards, A and Collins, J and Hutchison, RM and Unwin, A and Curiale, G and Baheti, G and Jones, M and Gallagher, D and Bullain, S},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e103364},
doi = {10.1002/alz70859_103364},
pmid = {41449506},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *tau Proteins ; Double-Blind Method ; *Drug Development ; Aged ; *Oligonucleotides, Antisense/therapeutic use ; Male ; Female ; Positron-Emission Tomography ; Middle Aged ; Amyloid beta-Peptides ; Biomarkers/cerebrospinal fluid ; },
abstract = {BACKGROUND: While the recent availability of amyloid-targeting disease-modifying therapies marks a major therapeutic advancement, significant unmet need remains for treatment of Alzheimer's disease (AD). Aβ deposition is believed to occur early in the pathogenesis of AD, yet clinicopathological studies have established that the density and distribution of tau neurofibrillary tangles are more closely associated with the severity of clinical impairment. Biogen is developing BIIB080, an antisense oligonucleotide (ASO) that inhibits translation of tau mRNAs into protein for the treatment of AD, based on the hypothesis that lowering the production of all tau species will reduce post-translationally modified forms of tau, including aggregates, leading to slowing or halting of disease progression. Exploratory analyses from the BIIB080 Phase 1b study (NCT03186989) demonstrated a marked effect of BIIB080 on CSF tau and tau PET biomarkers as well as consistently favorable trends in the high-dose groups on multiple clinical endpoints.

METHOD: CELIA (NCT05399888) is a randomized, double-blind, placebo-controlled, parallel-group Phase 2 study to further evaluate the efficacy, safety, and tolerability of BIIB080 in participants with early AD. The study enrolled 416 individuals aged 50-80 years, with MCI or mild AD dementia, Clinical Dementia Rating (CDR) global score of 0.5-1, Mini Mental State Examination (MMSE) score of 21-30, objective evidence of cognitive impairment at screening, and confirmed amyloid positivity. Participants were randomized to receive 1 of 3 dose regimens of intrathecal (IT) BIIB080 or placebo every 12 or 24 weeks during the 76-week placebo-controlled period. The primary endpoint will assess the dose-response in change from baseline to week-76 on the CDR-SB. The study includes two PET substudies looking at BIIB080 effects: using 18F-MK-6240 PET on tau aggregates and using 18F-florbetapir PET BIIB080 on cerebral amyloid aggregates.

RESULT: The Phase 2 CELIA study recently completed enrollment. Preliminary review of baseline characteristics demonstrates similarity to those in other recent early AD trials. A full characterization will be presented.

CONCLUSION: The ongoing Phase 2 CELIA trial will assess the efficacy, safety, and tolerability of BIIB080 compared to placebo in participants with early AD.},
}

Humans
*Alzheimer Disease/drug therapy
*tau Proteins
Double-Blind Method
*Drug Development
Aged
*Oligonucleotides, Antisense/therapeutic use
Male
Female
Positron-Emission Tomography
Middle Aged
Amyloid beta-Peptides
Biomarkers/cerebrospinal fluid

@article {pmid41449483,
year = {2025},
author = {Duncan, GB and Duke, TM and Johnson, SB and Dayley, CW and Hendrix, SB and Mallinckrodt, C and Dickson, SP},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103841},
doi = {10.1002/alz70856_103841},
pmid = {41449483},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/blood/diagnosis/diagnostic imaging/drug therapy ; *Biomarkers/blood ; *tau Proteins/blood ; Positron-Emission Tomography ; Disease Progression ; Amyloid beta-Peptides ; },
abstract = {BACKGROUND: Recent advances have been made in understanding the pathophysiology of Alzheimer's disease (AD) and the role played by biomarkers. Amyloid PET has been used for diagnosis and as the primary outcome to support accelerated approval in AD. However, amyloid PET is costly, time consuming, and equipment dependent. Therefore, we investigate the accuracy and sensitivity of plasma pTau as a convenient biomarker to predict clinical outcomes and disease progression in AD trials.

METHOD: Published data from anti-amyloid mAb studies were analyzed to assess the group-level sample-size weighted Pearson correlation between the treatment effects in plasma pT217, pT181 and clinical outcomes. The plasma pTau and clinical outcome correlation is compared to the corresponding correlation of amyloid PET with clinical outcomes in order to assess the relative merits of these biomarkers. To explore the potential of plasma pTau as a primary outcome, power calculation was performed to simulate proof-of-concept study designs on early drug development studies, assessing dose-response and sample size.

RESULT: We found that in the same studies in which amyloid PET was used to support accelerated approval applications, the group-level correlations of plasma pT217, pT181 with clinical outcome group-level effects were comparable to the corresponding correlations between amyloid PET and clinical outcomes. In addition, the Cohen's d effect sizes of plasma pT217 or pT181 as biomarker outcomes were greater than the Cohen's d values of clinical outcome assessments ADAS-Cog, ADCS-ADL, CDR-SB, and their clinical composite, leading to higher power or lower sample sizes. Plasma pT217 or pT181 is 3-fold more sensitive than clinical outcomes to measurement of disease progression, resulting in comparable power for one ninth of the sample size, since it is a squared relationship (see Figure).

CONCLUSION: These plasma pTau biomarkers that are less costly and easier to obtain, may provide appropriate reliability as a predictor of clinical outcomes, similar to amyloid PET. Plasma pTau biomarkers also have a greater standard effect size than clinical outcomes and are more sensitive in predicting disease progression. Therefore, plasma pTau biomarkers could support early phase clinical trials with smaller sample sizes than clinical outcomes, using a more accessible and cost-effective biomarker.},
}

Humans
*Alzheimer Disease/blood/diagnosis/diagnostic imaging/drug therapy
*Biomarkers/blood
*tau Proteins/blood
Positron-Emission Tomography
Disease Progression
Amyloid beta-Peptides

@article {pmid41449466,
year = {2025},
author = {Malta, SM and Bernardes, LMM and Silva, MH and Santos, ACC and Batista, LL and Rodrigues, TS and do Prado Mascarenhas, FA and Zanon, RG and Espindola, FS and Mendes-Silva, AP and Ueira-Vieira, C},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e103543},
doi = {10.1002/alz70859_103543},
pmid = {41449466},
issn = {1552-5279},
mesh = {*Amyloid beta-Peptides/metabolism ; *Peptide Fragments/metabolism ; *Kefir ; *Drug Development ; Animals ; *Neuroprotective Agents/pharmacology ; Peptides/pharmacology ; Humans ; Alzheimer Disease/drug therapy ; },
abstract = {BACKGROUND: Kefir is a probiotic-rich fermented milk beverage composed of a symbiotic consortium of bacteria and yeasts. Emerging evidence has shown its neuroprotective potential, including that of its derived metabolites and fractions, in mitigating β-amyloid (Aβ42)-induced neurotoxicity in cultured neuronal cells and neurodegeneration in Drosophila melanogaster models for Alzheimer's disease (AD). Building on these findings, we explored the in vitro effects of kefir-derived fractions and synthetic peptides on Aβ42 aggregation and disaggregation.

METHOD: Two kefir fractions, Ethyl Acetate (EtOAc) and <10kDa, and two kefir-derived peptides (KDPs) identified in our prior research were tested. For the preventive assay, Aβ42 (10 µM) was co-incubated with kefir fractions (0.25 mg/mL) or KDPs (1, 10 and 100 µM) for 24 hours, with fluorescence readings (Thioflavin T) taken hourly. For the treatment assay, Aβ42 was incubated alone for 48 hours to induce aggregation, followed by treatment with fractions or KDPs, with fluorescence readings taken after an additional 48-hour incubation. All experiments were performed in 96-well plates, with samples in quintuplicate. Statistical analysis was conducted using one-way ANOVA.

RESULT: Fluorescence intensity measurements revealed that, in the preventive assay, all treatments significantly reduced Aβ42 aggregation compared to the untreated control (p<0.0001). In the treatment assay, significant disruption of Aβ42 aggregation was observed with KDP-1 (p=0.0055) and KDP-2 (p<0.0001).

CONCLUSION: This study highlights the potential ability of kefir fractions and synthetic peptides to prevent and disrupt Aβ42 aggregation in vitro, supporting their therapeutic promise in neurodegenerative disorders. Further studies should explore their mechanisms of action and efficacy in vivo.},
}

*Amyloid beta-Peptides/metabolism
*Peptide Fragments/metabolism
*Kefir
*Drug Development
Animals
*Neuroprotective Agents/pharmacology
Peptides/pharmacology
Humans
Alzheimer Disease/drug therapy

@article {pmid41449442,
year = {2025},
author = {Darwish, M and Mason, JW and Stanworth, SW and Feng, X and Dirks, B and Raether, B and Pathak, SS},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e105893},
doi = {10.1002/alz70859_105893},
pmid = {41449442},
issn = {1552-5279},
mesh = {Humans ; Double-Blind Method ; Male ; Female ; Electrocardiography/drug effects ; Adult ; Middle Aged ; *Drug Development ; *Long QT Syndrome/chemically induced ; Healthy Volunteers ; Dose-Response Relationship, Drug ; },
abstract = {BACKGROUND: QT interval prolongation is a known adverse event of many psychotropic medications. ACP-204, a potent and selective inverse agonist/antagonist of serotonin 2A (5-HT2A), was developed for the treatment of Alzheimer's disease psychosis to have an improved pharmacological profile and lower risk of QT prolongation. This study evaluates the effect of ACP-204 on corrected QT (QTc) intervals and the relationship between plasma drug concentrations and time-matched change in QTc following single doses in healthy volunteers.

METHOD: QTc intervals were analyzed from randomized, placebo-controlled, double-blind, Phase 1 data in which healthy adult participants were randomized to single ascending oral doses of ACP-204 (10 to 180 mg) or placebo. Data from 12-lead electrocardiogram (ECG) assessments at screening, baseline, and up to 48 hours postdose were used to evaluate changes from baseline in Friderica-corrected QT (ΔQTcF) intervals. Concentration-effect modeling was used to analyze the relationship between plasma drug concentrations and time-matched changes in QTcF. QTc interval assessments were summarized descriptively and categorically.

RESULT: This analysis included 57 participants. A ΔQTcF >30 ms and ≤60 ms was observed in 1 participant in each of the 60, 130, and 180 mg cohorts; 1 participant in the 40 mg cohort had a ΔQTcF >60 ms. The QTcF interval did not exceed 450 ms at any time point for any participant, and no dose-response pattern was observed (Figure 1). The Fridericia heart rate correction met adequacy criterion; 89.5% of participants had QTcF versus RR interval slopes <|0.045|, exceeding the 50% requirement (Figure 2). Changes observed using concentration-effect modeling were small and benign (Figure 3A-B). After subtraction of placebo ΔQTcF, the upper limit of the confidence band remained below 10 ms throughout to the maximum observed concentration of ∼395 ng/mL. Model-predicted average placebo-adjusted ΔQTcF (ΔΔQTcF) at mean Cmax levels for all dose cohorts ranged from 3.17 ms (10 mg) to 0.47 ms (180 mg). The upper limit of the 2-sided 90% CI for ΔΔQTcF at 180 mg was 6.51 ms.

CONCLUSION: No meaningful increases in QTcF were observed in healthy participants after single-dose administration of ACP-204 (10-180 mg); specifically, there was no QTcF prolongation up to 180 mg.},
}

Humans
Double-Blind Method
Male
Female
Electrocardiography/drug effects
Adult
Middle Aged
*Drug Development
*Long QT Syndrome/chemically induced
Healthy Volunteers
Dose-Response Relationship, Drug

@article {pmid41449440,
year = {2025},
author = {Klein, G and Rabinovici, GD and Zetterberg, H and Tonietto, M and Bittner, T and Rukina, D and Alcaraz, F and Hofmann, C and Marchesi, M and Wojtowicz, J and Croney, R and Agnew, D and Abrantes, JA and Stark, FS and Ahlers, S and Delmar, P and Svoboda, H and Wiesel, I and Kulic, L},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e104288},
doi = {10.1002/alz70859_104288},
pmid = {41449440},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Double-Blind Method ; *Cognitive Dysfunction/drug therapy ; *Drug Development ; Male ; *Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage ; Female ; Aged ; Amyloid beta-Peptides ; Brain/diagnostic imaging/drug effects ; tau Proteins/cerebrospinal fluid ; Dose-Response Relationship, Drug ; },
abstract = {BACKGROUND: Trontinemab is a novel amyloid-targeting Brainshuttle™ monoclonal antibody specifically engineered for efficient transferrin receptor 1-mediated transport across the blood-brain barrier. It is currently under evaluation in the Phase Ib/IIa Brainshuttle™ AD study (NCT04639050) in participants with mild cognitive impairment due to Alzheimer's disease (AD) or mild-to-moderate AD.

METHOD: The Brainshuttle™ AD study is a randomized, double-blind, placebo-controlled, multiple ascending dose study designed to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of trontinemab following intravenous (IV) infusion. The study uses a staggered parallel-group design, with participants recruited to four initial dose cohorts: 0.2 mg/kg (Cohort 1), 0.6 mg/kg (Cohort 2), 1.8 mg/kg (Cohort 3), and 3.6 mg/kg (Cohort 4). A minimum of 10 study participants per dose cohort are randomized in a 4:1 ratio to receive either trontinemab or placebo IV every 4 weeks for a total of seven doses in Part 1 of the study. In a dose-expansion study (Part 2), an additional 60 participants are enrolled in each of Cohorts 3 and 4. Biomarker results, including global and regional amyloid positron emission tomography (PET), volumetric magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and plasma will be presented. Plasma and CSF samples are analyzed using the Roche Elecsys NeuroToolKit.

RESULT: An interim analysis (data snapshot: Sep 2, 2024) revealed dose-dependent amyloid plaque lowering and downstream effects on biomarkers across all active doses. Part 1 Cohort 4 exhibited very rapid amyloid depletion: -89 centiloids after 12 weeks (n=13), and -107 centiloids after 28 weeks (n=12). CSF downstream markers including total tau, phosphorylated tau181, and neurogranin were reduced by 30%, 34%, and 29%, respectively by Week 25 in the 3.6 mg/kg dose cohort in Part 1. Updated results from the most recent data snapshot will include available 28-week PET data as well as MRI, CSF, and plasma results from Part 2 of the study.

CONCLUSION: Preliminary results from the ongoing Brainshuttle™ AD study suggest that rapid and deep amyloid reduction can be achieved in most participants at 1.8 and 3.6 mg/kg doses within ≤28 weeks. New biomarker data will be presented to further evaluate trontinemab's continued development as a potential AD treatment.},
}

Humans
*Alzheimer Disease/drug therapy
Double-Blind Method
*Cognitive Dysfunction/drug therapy
*Drug Development
Male
*Antibodies, Monoclonal, Humanized/therapeutic use/administration & dosage
Female
Aged
Amyloid beta-Peptides
Brain/diagnostic imaging/drug effects
tau Proteins/cerebrospinal fluid
Dose-Response Relationship, Drug

@article {pmid41449319,
year = {2025},
author = {Panda, S and Singh, SK and Bashir, B and Pal, B and Vishwas, S and Kaur, J},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102526},
doi = {10.1002/alz70859_102526},
pmid = {41449319},
issn = {1552-5279},
mesh = {Animals ; Rats ; *Alzheimer Disease/drug therapy ; *Drug Development ; *Neuroprotective Agents/pharmacology ; *Drug Delivery Systems ; Oxidative Stress/drug effects ; *Quercetin/analogs & derivatives/pharmacology/administration & dosage ; Blood-Brain Barrier/metabolism/drug effects ; Disease Models, Animal ; Male ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and behavioral changes. The disease is marked by the accumulation of amyloid-beta plaques and tau tangles, which disrupt neuronal function and lead to cell death. Neuroinflammation, oxidative stress, and synaptic dysfunction further contribute to AD pathology. Various studies evaluate the therapeutic properties of the phytoconstituents like curcumin, piperine, resveratrol, berberine and quercetin for the treatment of AD. Among these phytoconstituents, Isorhamnetin (IH) is reported to have neuroprotective effects against AD by inhibiting the expression of p-JNK, p-p38, and p-NFκB proteins. Studies showed that IH mediates a protective effect against oxidative stress and neuroinflammation. Despite its prospects, the therapeutic use of IH at target sites is limited due to their poor solubility, less bioavailability and poor blood brain barrier (BBB) penetration.

METHOD: To address these limitations, a IH loaded self-emulsifying drug delivery system (SNEDDS) was developed which improved drug loading, stability, bioavailability, and BBB permeability. Further, pharmacodynamic study were conducted using Morris Water Maize test to assess the cognitive performance of rats. Additionally biochemical assessment were performed to measure key markers of AD.

RESULT: The optimized IH-loaded SNEDDS formulation demonstrated a droplet size of 59.46 nm, polydispersity index of 0.3, zeta potential of -19 mV, and 96% drug loading respectively. Pharmacodynamic evaluations showed significant improvements in cognitive and motor functions in rats at high doses. Biochemical analysis revealed that the formulation effectively reduced AChE levels, amyloid-beta, oxidative stress, and neuroinflammation.

CONCLUSION: IH-loaded SNEDDS served as a therapeutic approach in the management of AD.},
}

Animals
Rats
*Alzheimer Disease/drug therapy
*Drug Development
*Neuroprotective Agents/pharmacology
*Drug Delivery Systems
Oxidative Stress/drug effects
*Quercetin/analogs & derivatives/pharmacology/administration & dosage
Blood-Brain Barrier/metabolism/drug effects
Disease Models, Animal
Male

@article {pmid41449314,
year = {2025},
author = {Georgiou, E and Grigorova, P and Sen, SE and Miller, AM and O'Connor, A and Kinchin, I and Leroi, I},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e101630},
doi = {10.1002/alz70858_101630},
pmid = {41449314},
issn = {1552-5279},
mesh = {Humans ; Ireland ; Feasibility Studies ; *Dementia/therapy/psychology ; *Alzheimer Disease/psychology/therapy/drug therapy ; Retrospective Studies ; Delivery of Health Care ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a leading cause of cognitive decline, and the recent European approval of disease-modifying therapies (DMTs) like Donanemab and Lecanemab offers new hope for slowing its progression. However, healthcare systems across Europe, including Ireland, are unprepared for their real-world implementation. Challenges include equitable access, infrastructure readiness, and treatment logistics. This study aims to evaluate the feasibility of implementing DMTs across public and private healthcare sectors in Ireland, positioning it as a stepping stone toward broader European readiness.

METHOD: This multi-center observational feasibility study will assess DMT implementation readiness across Irish centers (Dublin, Waterford, Cork, Galway). The study employs patient journey mapping using retrospective and hypothetical data, alongside evaluations of key process measures, including referral timelines, biomarker verification, infusion readiness, and follow-up protocols. Graph-theory modeling will visualize patient pathways and highlight system inefficiencies.

RESULTS: The study is expected to reveal disparities in DMT access, logistical bottlenecks, and enablers for scalable implementation. Graph-based modeling will provide actionable insights to optimize patient pathways and healthcare delivery frameworks. Stakeholder feedback will inform patient-centered approaches and address equity challenges.

CONCLUSION: This feasibility study addresses the critical need for preparedness in integrating DMTs for AD, which were recently approved in Europe but remain underutilized due to systemic barriers. By generating actionable insights and laying the groundwork for national guidelines, this project not only advances Ireland's readiness but also serves as a model for other European countries seeking to adopt transformative therapies for Alzheimer's disease.},
}

Humans
Ireland
Feasibility Studies
*Dementia/therapy/psychology
*Alzheimer Disease/psychology/therapy/drug therapy
Retrospective Studies
Delivery of Health Care

@article {pmid41449301,
year = {2025},
author = {Moughamian, A and Kile, S and Kim, J and Sengupta, A and Pickett, A and Cheung, J and Urban, T and Zhao, C and Vallee, L and Mukundan, G and Sudat, S},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102433},
doi = {10.1002/alz70859_102433},
pmid = {41449301},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/drug therapy ; *Drug Development ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use ; Aged, 80 and over ; *Cognitive Dysfunction/drug therapy ; Middle Aged ; Apolipoprotein E4/genetics ; },
abstract = {BACKGROUND: Lecanemab was the first disease modifying therapy for Alzheimer's disease to receive full FDA approval but is associated with the serious side-effect of ARIA (amyloid related imaging abnormalities). Due to the novelty of lecanemab and ARIA, uncertainty exists regarding the frequency and severity of ARIA in clinical practice. Here we summarize our experience with lecanemab in a community-based healthcare system.

METHOD: Data collection was approved by the Sutter Health IRB. All subjects were screened at a memory clinic. Eligibility for treatment was determined by the FDA labelling and Appropriate Use Recommendations were followed with a few exceptions. We present data on patients who received lecanemab between July 2023 and June 2024 since these patients received at least 6 months of lecanemab treatment, the highest risk time for ARIA.

RESULT: 210 patients were treated; the mean age was 75, 52% female, 70% mild cognitive impairment and 30% mild dementia. 37% were ApoE4 non-carriers, 56% ApoE4 heterozygotes and 6% ApoE4 homozygotes. 36% of patients experienced infusions reactions (91% mild, 8% moderate and 1% severe). Lecanemab was discontinued in 14% of patients. There were 5 deaths, none attributed to lecanemab treatment. There were 33 cases (15.7%) of ARIA including ARIA-E, ARIA-H and ARIA-E with ARIA-H. 29 (13.8%) had ARIA-H and 16 (7.6%) had ARIA-E. ARIA occurred in 8 of 78 ApoE4 non-carriers, 19 of 118 ApoE4 heterozygotes and 5 of 13 ApoE4 homozygotes. 8 cases of severe radiographic ARIA occurred (4 ApoE4 homozygotes, 3 ApoE4 heterozygotes and 1 ApoE4 non-carrier). 3 cases of ARIA were symptomatic. A majority of ARIA occurred in the posterior cortex and ARIA-H often occurred in the same region of ARIA-E.

CONCLUSION: Our data show that lecanemab can be safely delivered in a large community-based healthcare system. Compared to the phase 3 CLARITY-AD trial, we report higher rates of infusions related reactions but lower rates of ARIA. Our cohort contains fewer ApoE4 homozygotes (6%) compared to CLARITY-AD (16%) which likely reduces our ARIA rates. However, we observe lower rates of ARIA in ApoE4 non-carriers and ApoE4 heterozygotes compared to CLARITY-AD, supporting that lecanemab can be safely administered in a community setting.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/drug therapy
*Drug Development
*Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use
Aged, 80 and over
*Cognitive Dysfunction/drug therapy
Middle Aged
Apolipoprotein E4/genetics

@article {pmid41449132,
year = {2025},
author = {Bregman, N and Nathan, T and Shir, D and Hay-Levy, M and Trabulus, N and Bar-David, A and Wolpe, G and Abu-Awad, A and Alcalay, Y and Ash, E and Shiner, T},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102792},
doi = {10.1002/alz70859_102792},
pmid = {41449132},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/drug therapy/cerebrospinal fluid ; Aged ; Amyloid beta-Peptides ; tau Proteins/cerebrospinal fluid/blood ; Biomarkers/cerebrospinal fluid/blood ; *Drug Development ; Middle Aged ; Aged, 80 and over ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Mental Status and Dementia Tests ; Apolipoprotein E4/genetics ; Treatment Outcome ; Follow-Up Studies ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a significant impact on patients and healthcare systems. Lecanemab, a monoclonal antibody targeting amyloid beta, has recently been approved for early-stage AD, offering potential for disease modification. This report examines the demographic characteristics, treatment responses, and safety profile of early-stage AD patients treated with Lecanemab at the Tel Aviv Medical Center (TLVMC), focusing on 6-month follow-up outcomes.

METHOD: Since November 2023, Lecanemab has been administered to early-stage AD patients at TLVMC. Data collected included baseline demographics, ApoE4 status, CSF biomarkers (t-tau, p-tau181, Aβ42), plasma p-tau181 levels, and Mini-Mental State Examination (MMSE) scores. Patients were monitored for amyloid-related imaging abnormalities (ARIA), and cognitive outcomes were assessed at 6 months. This report summarizes data for patients who completed the 6-month follow-up by January 2025.

RESULT: By January 2025, 45 out of 85 patients had completed the 6-month visit. The mean age was 73 years (SD = 7.2), with 53% women and 51% ApoEε4 carriers. Mean baseline CSF biomarker levels (pg/ml): t-tau = 580 (SD = 268), p-tau181 = 194 (SD = 461), and Aβ42 = 333 (SD = 166). Plasma p-tau181 levels (n=27) had a mean value of 32.3 pg/ml (SD = 10.5). The mean baseline MMSE score was 24.02 (SD = 2.59). Plasma p-tau181 levels were significantly correlated with baseline MMSE scores (r = -0.429, p = 0.023). At 6 months, the mean MMSE score decreased to 22.48 (SD = 3.92), a significant decline of 1.47 points from baseline (p = 0.009). Younger patients (<75 years) showed a statistically significant decline in MMSE score (p = 0.007), while older patients (≥75 years) did not. Seven patients (15.5%) developed asymptomatic ARIA-H during the first 6 months.

CONCLUSION: This 6-month follow-up highlights Lecanemab's potential to preserve cognitive function in early-stage AD, with a lower incidence of ARIA than reported in trials. These findings emphasize the importance of real-world evidence in shaping clinical practice for disease-modifying therapies.},
}

Humans
Female
Male
*Alzheimer Disease/drug therapy/cerebrospinal fluid
Aged
Amyloid beta-Peptides
tau Proteins/cerebrospinal fluid/blood
Biomarkers/cerebrospinal fluid/blood
*Drug Development
Middle Aged
Aged, 80 and over
*Antibodies, Monoclonal, Humanized/therapeutic use
Mental Status and Dementia Tests
Apolipoprotein E4/genetics
Treatment Outcome
Follow-Up Studies

@article {pmid41449130,
year = {2025},
author = {Mares, JA and Guo, J and Nuriel, T},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e103473},
doi = {10.1002/alz70856_103473},
pmid = {41449130},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics/diagnostic imaging ; Male ; *Apolipoprotein E4/genetics ; Female ; Magnetic Resonance Imaging ; *Biomarkers ; Aged ; Positron-Emission Tomography ; Neuroimaging ; *Brain/diagnostic imaging/pathology ; *Cognitive Dysfunction/genetics/diagnostic imaging ; tau Proteins/metabolism ; Heterozygote ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Carriers of the apolipoprotein E ε4 (APOE4) allele are at an increased risk of developing Alzheimer's disease (AD) and display an earlier age of onset compared to non-carriers who develop the disease. While researchers have extensively characterized the impact of APOE4 on the susceptibility of AD, little is known about the differences in disease etiology and presentation in APOE4 carriers vs. non-carriers.

METHOD: In order to investigate these differences, we performed a broad analysis of neuroimaging biomarkers in APOE4 carriers vs. non-carriers present in the ADNI cohort. We also have analyzed this data using a novel deep learning method called DeepContrast, which uses artificial intelligence to identify functional brain activity signatures in structural MRI scans.

RESULT: We observed differences between APOE4 carriers vs. non-carriers in several neuroimaging readouts, including Ab-PET, Tau-PET, FDG-PET, structural MRI, and FLAIR MRI. These differences were variable based on sex and age. Interestingly, when we compared cognitively unimpaired ADNI participants who converted to MCI or AD to those who did not, we observed APOE4-dependent differences that may point to specific pathologies that mediate MCI/AD conversion in APOE4 carriers vs. non-carriers. In addition, we also have exciting new data showing distinct differences in APOE4 carriers vs. non-carriers from ADNI using DeepContrast.

CONCLUSION: These observations of pathological heterogeneity between APOE4 carriers vs. non-carriers reveal significant differences in disease pathogenesis between these two groups, which may have important implications with regard to the diagnosis and treatment of AD in different at-risk populations.},
}

Humans
*Alzheimer Disease/genetics/diagnostic imaging
Male
*Apolipoprotein E4/genetics
Female
Magnetic Resonance Imaging
*Biomarkers
Aged
Positron-Emission Tomography
Neuroimaging
*Brain/diagnostic imaging/pathology
*Cognitive Dysfunction/genetics/diagnostic imaging
tau Proteins/metabolism
Heterozygote
Middle Aged
Aged, 80 and over

@article {pmid41449127,
year = {2025},
author = {Villar, AA and Villino-Rodríguez, RA and Espinoza-Vinces, C and Pérez-Prol, C and Jimenez-Huete, A and Dominguez, P and Riverol, M},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102269},
doi = {10.1002/alz70859_102269},
pmid = {41449127},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Retrospective Studies ; Middle Aged ; Aged, 80 and over ; *Drug Development ; Magnetic Resonance Imaging ; *Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use ; Brain/diagnostic imaging ; },
abstract = {BACKGROUND: Amyloid-related imaging abnormalities (ARIAs) are complications associated with anti-amyloid therapy in Alzheimer's disease (AD). ARIAs include ARIA-edema (ARIA-E) and ARIA-hemorrhage (ARIA-H), which may present asymptomatically or with mild symptoms. Identifying risk factors, such as the ApoE4 genotype, and understanding the clinical course of ARIAs are critical for optimizing treatment outcomes in AD patients undergoing anti-amyloid therapy.

METHOD: A retrospective observational analysis was conducted on data from patients participating in clinical trials involving anti-amyloid antibodies (Aducanumab, Gantenerumab, Crenezumab). Demographic data, ApoE genotyping, cardiovascular risk factors, treatment initiation dates, and occurrence of ARIAs were recorded. ARIA events were classified as ARIA-E or ARIA-H, and associated symptoms, time of onset, and resolution were documented. Brain MRI was used to monitor ARIA progression and persistence.

RESULT: The study included 52 patients (mean age: 68.6 years; range: 52-85), 42.3% of whom were female. ARIAs were identified in 9 patients, accounting for 15 events: 7 treated with Aducanumab and 2 with Gantenerumab, while none occurred with Crenezumab. Among these, 5 cases involved ARIA-E, 9 involved ARIA-H, and 1 patient exhibited both. Most events were asymptomatic or associated with very mild symptoms, with no treatment discontinuation required. ARIA-E typically resolved spontaneously within 4-8 weeks, while ARIA-H persisted on follow-up MRIs. Events generally occurred between weeks 20 and 39 of treatment, with ARIA-H appearing later in some exceptional cases. A strong correlation with the ApoE4 genotype was observed, as most patients developing ARIAs carried at least one ApoE4 allele.

CONCLUSION: Patients undergoing anti-amyloid therapy are at risk of developing ARIAs, particularly those carrying the ApoE4 genotype. ARIAs are generally asymptomatic, do not necessitate treatment discontinuation, and show differing courses depending on the subtype: ARIA-E resolves spontaneously, while ARIA-H persists. Aducanumab was associated with the highest frequency of ARIA events. These findings underscore the importance of regular MRI monitoring and patient-specific management strategies to mitigate complications and optimize therapy outcomes.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/drug therapy/diagnostic imaging
Retrospective Studies
Middle Aged
Aged, 80 and over
*Drug Development
Magnetic Resonance Imaging
*Antibodies, Monoclonal, Humanized/adverse effects/therapeutic use
Brain/diagnostic imaging

@article {pmid41449116,
year = {2025},
author = {Clayton, B and Massey, SM and Chu, S and Mason, ER and Bissel, SJ and Bedford, LM and Rizzo, SJS and Mesecar, AD and Kaiser, BL and Lendy, EK and Lamb, BT and Palkowitz, AD and Richardson, TI},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e103518},
doi = {10.1002/alz70859_103518},
pmid = {41449116},
issn = {1552-5279},
mesh = {Humans ; *Drug Development ; *Phospholipase C gamma/genetics/metabolism ; *Alzheimer Disease/drug therapy/genetics ; Animals ; Microglia/drug effects/metabolism ; Structure-Activity Relationship ; High-Throughput Screening Assays ; },
abstract = {BACKGROUND: The role of microglia in neuroinflammation is widely recognized as a key contributor to the pathogenesis of Alzheimer's disease (AD). Genome-wide association studies have identified PLCγ2 as a key contributor, with specific variants conferring either risk or protection. Notably, the protective PLCγ2•P522R variant is associated with increased mRNA expression, protein levels, and innate activity, whereas the risk variant PLCγ2•M28L shows the opposite trend. Based on these findings, we hypothesize that small molecules capable of enhancing PLCγ2 expression or directly activating the protein could mimic the protective effects of the P522R variant. Such an approach may represent a promising therapeutic strategy to mitigate disease progression and cognitive decline in AD patients.

METHOD: We performed high-throughput screening including DNA Encoded Library (DEL) and Affinity Selection Mass Spectrometry (ASMS) using full-length protein to identify novel small molecules which bind to PLCγ2. Target engagement was confirmed using Differential Scanning Fluorimetry (DSF) and Cellular Thermal Shift Assay (CETSA). Structure activity relationship (SAR) studies were performed to synthesize analogs and optimize for binding and cellular pharmacology in IP-One and phagocytosis assays. Top compounds have been studied in vivo to assess pharmacokinetic properties as well as impact on neuroinflammation.

RESULT: Novel PLCγ2 activators have been discovered and preliminary optimization has been completed. These compounds have shown positive results for target engagement, biochemical activity, and cellular pharmacology. In silico predictions indicated the molecule structures are suitable CNS drug discovery program starting points.

CONCLUSION: Activation of PLCγ2 is a novel therapeutic strategy for treatment of AD. We identified structurally distinct molecular scaffolds capable of enzyme activation and cellular activity. Recommendations for use of probe molecules in target validation studies and the development of lead-like molecules for clinical studies will be made.},
}

Humans
*Drug Development
*Phospholipase C gamma/genetics/metabolism
*Alzheimer Disease/drug therapy/genetics
Animals
Microglia/drug effects/metabolism
Structure-Activity Relationship
High-Throughput Screening Assays

@article {pmid41449112,
year = {2025},
author = {Jung, JH and Kong, N and Lee, S},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e104595},
doi = {10.1002/alz70857_104595},
pmid = {41449112},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *tau Proteins/metabolism ; Positron-Emission Tomography ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; Biomarkers/metabolism ; *Cognitive Dysfunction/metabolism/diagnostic imaging ; Cross-Sectional Studies ; Longitudinal Studies ; *Blood Pressure/physiology ; Aged, 80 and over ; },
abstract = {BACKGROUND: Aging is accompanied by vascular changes, notably arterial stiffness, which is reflected by pulse pressure (PP). Elevated PP has been linked to cardiovascular and cerebrovascular diseases, as well as cognitive decline and dementia. However, its specific role in Alzheimer's disease (AD) development and progression remains underexplored. This study investigates the association between baseline PP and key AD biomarkers-amyloid-beta (Aβ) and tau deposition-and cognitive decline.

METHOD: This study utilized data from 1,690 cognitively unimpaired older adults participating in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Biomarkers were assessed using positron emission tomography (PET) imaging for Aβ and tau (n = 411) deposition. Cognitive function was evaluated using the Preclinical Alzheimer Cognitive Composite (PACC). Cross-sectional analyses were conducted to examine associations, with linear regression adjusted for age, sex, education, and APOE4 status.

RESULT: We revealed that elevated PP was significantly associated with increased global and inferior temporal tau deposition (standardized β = 0.11, p =  0.020; standardized β = 0.12, p =  0.012). Moreover, elevated PP was also associated with higher Aβ deposition (standardized β = 0.06, p =  0.011) and with lower PACC (standardized β = -0.05, p =  0.034). APOE4 status moderated the relationship between PP and tau deposition; in APOE4 carriers, higher PP was strongly associated with tau accumulation, while no significant relationship was observed in non-carriers.

CONCLUSION: These findings underscore the importance of arterial stiffness as a contributor to AD pathology and lower cognition, particularly in individuals with genetic susceptibility. By revealing how PP interacts with APOE4 to influence tau deposition, this study emphasizes the need for targeted interventions addressing vascular health to mitigate AD progression. Future research should further explore mechanisms linking vascular health and AD biomarkers to refine preventative strategies.},
}

Humans
Male
Female
Aged
*tau Proteins/metabolism
Positron-Emission Tomography
*Amyloid beta-Peptides/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism
Biomarkers/metabolism
*Cognitive Dysfunction/metabolism/diagnostic imaging
Cross-Sectional Studies
Longitudinal Studies
*Blood Pressure/physiology
Aged, 80 and over

@article {pmid41449106,
year = {2025},
author = {de Oliveira Alves, J and Salomão, MHQC},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102310},
doi = {10.1002/alz70859_102310},
pmid = {41449106},
issn = {1552-5279},
mesh = {Humans ; *Antipsychotic Agents/therapeutic use ; *Dementia/drug therapy/psychology ; *Drug Development ; Aggression/drug effects ; Psychomotor Agitation/drug therapy ; },
abstract = {BACKGROUND: Dementia affects approximately 47 million people globally. Behavioral and psychological symptoms of dementia (BPSD), such as agitation, aggression, delusions, and hallucinations, are common during the progression of the disease and directly impact the quality of life of patients, families, and caregivers (CALSOLARO, 2021; FRANCHI, 2016). This study analyzes pharmacological management strategies for these cases.

METHOD: A comparative analysis was conducted using three scientific articles from the Medline database that address pharmacological treatment in patients with dementia.

RESULT: Antipsychotics are frequently used to treat agitation, aggression, and psychosis in dementia. Typical antipsychotics: Haloperidol is widely used for delirium but presents a high risk of side effects, such as sedation, extrapyramidal symptoms, and increased mortality, being recommended only in emergencies (CALSOLARO, 2021). Atypical antipsychotics: These are more tolerable, with a lower incidence of extrapyramidal symptoms. Risperidone is effective in managing agitation and aggression (FRANCHI, 2016) and is indicated for moderate to severe Alzheimer's cases (CALSOLARO, 2021). Aripiprazole reduces psychotic symptoms with fewer side effects (MINTZER, 2007), while quetiapine is preferred for patients with Parkinsonian characteristics (CALSOLARO, 2021). However, the prolonged use of atypical antipsychotics is associated with increased mortality and cerebrovascular events (CALSOLARO, 2021). Antidepressants: SSRIs, such as citalopram, may help with agitation but carry the risk of cognitive decline and QT interval prolongation (FRANCHI, 2016). Acetylcholinesterase inhibitors and memantine: Rivastigmine and memantine reduce agitation and aggression; donepezil provides small improvements (FRANCHI, 2016). Analgesics: Paracetamol alleviates pain and reduces neuropsychiatric symptoms, while opioids decrease agitation (FRANCHI, 2016). Anticonvulsants: Carbamazepine showed limited benefits, but its tolerability restricts its use; valproate did not demonstrate efficacy (FRANCHI, 2016).

CONCLUSION: Pharmacological management should be individualized, considering symptoms, comorbidities, and frailty. Medications should be used at the lowest effective dose and for the shortest possible duration to minimize side effects.},
}

Humans
*Antipsychotic Agents/therapeutic use
*Dementia/drug therapy/psychology
*Drug Development
Aggression/drug effects
Psychomotor Agitation/drug therapy

@article {pmid41449103,
year = {2025},
author = {Kim, F and Xi, T and Lee, HJ and Rock, JA and Kim, S and Choung, JJ},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e107781},
doi = {10.1002/alz70859_107781},
pmid = {41449103},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy/blood ; Male ; Female ; Double-Blind Method ; Aged ; *Phosphodiesterase 5 Inhibitors/therapeutic use ; Biomarkers/blood ; tau Proteins/blood ; *Drug Development ; *Sulfonamides/therapeutic use ; Middle Aged ; Treatment Outcome ; Aged, 80 and over ; },
abstract = {BACKGROUND: AR1001 (mirodenafil), a second-generation oral phosphodiesterase 5 (PDE5) inhibitor, is being investigated as a disease-modifying therapy for Alzheimer's disease (AD). The phase 2 trial (AR1001-ADP2-US01) aimed to evaluate the safety and efficacy of AR1001 in patients with mild to moderate AD. After 26 weeks of once-daily oral dosing, 10 mg and 30 mg AR1001 demonstrated acceptable safety profiles in this population. While there were no significant differences between the treatment groups for the primary endpoint, Alzheimer's Disease Assessment Scale, cognitive subscale 13 (ADAS-Cog-13) at Week 26, plasma ptau-181 and ptau-217 AD biomarkers were significantly reduced in the 30 mg group compared to placebo.

METHOD: In this double-blind, randomized, placebo-controlled, parallel-group trial, 210 patients diagnosed with mild to moderate AD were randomized to receive either placebo, AR1001 10 mg, or AR1001 30 mg. Participants were administered treatment once-daily for 26 weeks. Participants were diagnosed clinically based on 2011 National Institute of Aging and Alzheimer's Associations criteria and were allowed to be on concomitant AD medication such as acetylcholinesterase inhibitors and NMDA receptor antagonists with at least 3 months of stable dose prior to screening. Pre-specified subgroup analyses based on concomitant AD medication were conducted for ADAS-Cog 13 and key plasma biomarkers, including ptau-181 and ptau-217.

RESULT: Sixty-seven and 69 participants were assigned to the placebo and AR1001 30 mg groups, respectively. At baseline, 36 of 67 (51.4%) participants on placebo and 46 of 69 (65.7%) participants on 30 mg AR1001 were on concomitant AD medication. Participants without concomitant AD medication treated with AR1001 30 mg (monotherapy) demonstrated a statistically significant improvement of 4.019 points over baseline at Week 26 (p=0.012) on ADAS-Cog 13. AR1001 30 mg monotherapy group also demonstrated reductions of 1.361 pg/ml in plasma ptau-181 (p=0.023) and 0.426 pg/mL in plasma ptau-217 compared to placebo at Week 26.

CONCLUSION: The subgroup analysis of participants on AR1001 30 mg without concomitant AD medication suggests potential for AR1001 as a monotherapy for the treatment of Alzheimer's disease.},
}

Humans
*Alzheimer Disease/drug therapy/blood
Male
Female
Double-Blind Method
Aged
*Phosphodiesterase 5 Inhibitors/therapeutic use
Biomarkers/blood
tau Proteins/blood
*Drug Development
*Sulfonamides/therapeutic use
Middle Aged
Treatment Outcome
Aged, 80 and over

@article {pmid41449100,
year = {2025},
author = {Lizama, BN and Pandey, K and Cho, E and Caldwell, J and Caro, VD and Duong, DM and Shin, R and Levey, AI and Seyfried, NT and Grundman, M and Teunissen, CE and Caggiano, AO and Hamby, ME},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102120},
doi = {10.1002/alz70859_102120},
pmid = {41449100},
issn = {1552-5279},
mesh = {Humans ; Double-Blind Method ; Male ; Female ; *Alzheimer Disease/drug therapy/cerebrospinal fluid ; Aged ; *Drug Development ; *Cognitive Dysfunction/drug therapy ; Receptors, sigma ; tau Proteins/blood/cerebrospinal fluid ; Middle Aged ; },
abstract = {BACKGROUND: Participants with Alzheimer's disease (AD) treated with sigma-2 receptor (S2R) modulator zervimesine (CT1812) exhibited slowing (39% in mITT, 95% in a pre-specified plasma-pTau217 subgroup (below-median at baseline)) of cognitive decline (ADAS-Cog11) compared to placebo in the SHINE trial (NCT03507790, COG0201). Given favorable clinical outcomes in the below-median pTau217 subgroup, correlation analysis of the CSF proteome with ADAS-Cog11 was performed to elucidate mechanisms of zervimesine-mediated preservation of cognition.

METHOD: SHINE was a Phase 2 randomized, double-blind, placebo-controlled study. Participants (N=152) received a daily oral dose of zervimesine (100 or 300 mg) or placebo for 6-months (end-of-study). The median baseline plasma-pTau217 concentration (ALZpath, SIMOA) designated participants into subgroups below median (<1 pg/mL, N=69) or above/equal median (≥1 pg/mL, N=69). A proteomics sub-study of 45 participants was performed (tandem-mass tag mass spectrometry, TMT-MS) of baseline and 6-month CSF. CSF from treatment-compliant participants (N=43 mITT, N=17 below-median) were used for further analyses. Pearson correlation analysis was performed with protein change-from-baseline (CFB) to ADAS-Cog11 CFB. Pathway analyses (STRING, Metacore) were performed on correlated proteins (p≤0.01).

RESULT: The previously-reported mITT CSF cognitive correlates were compared to those in the below-median pTau217 subgroup that demonstrated greater cognitive benefit with zervimesine versus placebo. In this subgroup, 106 proteins correlated with ADAS-Cog11 (p≤0.01), exhibiting enrichment in amyloid biology and immune response pathways (p≤0.05). To elucidate the biological underpinnings of robust pharmacodynamic correlates of cognitive improvement, pathway analysis was performed on 62 proteins that correlated with ADAS-Cog11 (p≤0.01) in both mITT and below-median pTau217 subgroup (excluding correlates (p≤0.01) in the subgroup that did not exhibit cognitive benefit with zervimesine). These 62 proteins were enriched in immune response, complement, and synapse biology pathways (FDR≤0.05).

CONCLUSION: In a pre-specified subgroup exhibiting 95% slowing of cognitive impairment with zervimesine, we identified protein correlates of cognition related to amyloid biology, supporting zervimesine mechanism of action. Enriching the mITT analysis with correlates from this biomarker-defined patient population reinforced observations of immune response and synaptic pathways that correlate with cognition in both mITT and below-median pTau217 subgroup. These biomarker findings paired with positive clinical outcomes support the further clinical development of zervimesine for AD.},
}

Humans
Double-Blind Method
Male
Female
*Alzheimer Disease/drug therapy/cerebrospinal fluid
Aged
*Drug Development
*Cognitive Dysfunction/drug therapy
Receptors, sigma
tau Proteins/blood/cerebrospinal fluid
Middle Aged

@article {pmid41449094,
year = {2025},
author = {Aro, OP and Ogunsuyi, OB and Oboh, G},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106225},
doi = {10.1002/alz70859_106225},
pmid = {41449094},
issn = {1552-5279},
mesh = {Animals ; *Drug Development ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Cockroaches ; *Brain/metabolism/drug effects ; *Antioxidants/pharmacology ; Streptozocin ; Seeds ; Alzheimer Disease/metabolism ; },
abstract = {BACKGROUND: Diabetes is a major risk factor for Alzheimer's disease (AD), with shared pathological mechanisms including insulin resistance, oxidative stress, mitochondrial dysfunction, neuroinflammation, and impaired brain energy metabolism. Chronic hyperglycemia accelerates cognitive decline by promoting amyloid-beta aggregation and tau hyperphosphorylation. Given the rising global prevalence of diabetes and its impact on neurodegeneration, plant-based interventions with antioxidant and metabolic-modulating properties hold promise for therapeutic development.

METHOD: Cockroaches were divided into six groups: control, STZ-induced, STZ+0.5% raw seeds, STZ+1% raw seeds, STZ+0.5% fermented seeds, and STZ+1% fermented seeds. Brain homogenates were analyzed for glucose, triglyceride, reactive oxygen species (ROS), and total thiol levels, biomarkers linked to metabolic and neurodegenerative disorders.

RESULT: STZ-induced cockroaches exhibited significant (p<0.05) elevations in glucose and ROS levels, along with a decline in total thiol content, indicative of oxidative damage. Treatment with tamarind seeds counteracted these effects, reducing ROS and glucose levels while increasing thiol content, suggesting enhanced antioxidant capacity. Survival rates were also improved in treated groups.

CONCLUSION: Tamarind seed supplementation mitigated metabolic stress and oxidative damage, processes central to both diabetes and AD progression. These findings underscore the therapeutic potential of tamarind seeds in modulating key metabolic and neuroprotective pathways relevant to AD. Further research is needed to explore their impact on amyloid-beta clearance, tau pathology, and neuroinflammatory responses in diabetic neurodegeneration models.},
}

Animals
*Drug Development
Oxidative Stress/drug effects
Reactive Oxygen Species/metabolism
Cockroaches
*Brain/metabolism/drug effects
*Antioxidants/pharmacology
Streptozocin
Seeds
Alzheimer Disease/metabolism

@article {pmid41449091,
year = {2025},
author = {Wang, L and Park, E and He, C and Abbasi, AZ and Rajakumar, RCJ and Huang, S and Fraser, PE and Henderson, JT and Wu, XY},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e104173},
doi = {10.1002/alz70859_104173},
pmid = {41449091},
issn = {1552-5279},
mesh = {Animals ; *Alzheimer Disease/drug therapy ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Nanoparticles ; *Drug Development ; Brain/metabolism ; Manganese Compounds ; Blood-Brain Barrier/metabolism ; Humans ; Neuroinflammatory Diseases ; },
abstract = {BACKGROUND: Neuroinflammation plays a causal role in neurodegenerative Alzheimer's disease (AD); it occurs long before clinical onset of AD.[1] Therefore, early detection of neuroinflammation is critical for early intervention before the irreversible neurodegeneration happens. To address this pressing need, our group has developed multifunctional bioreactive nanoparticles, consisting of blood-brain barrier-penetrating terpolymer and MnO2 nanoparticles and conjugated anti-Ab antibody (Ab-TP-MDNP). The system reduced oxidative stress and produced oxygen and paramagnetic Mn[2+] ions, thereby remodeling the brain microenvironment and enabling sensitive detection of early neuroinflammation prior to Ab plague formation in an APP transgenic TgCRND8+ AD mouse model.[2] We also demonstrated its effects on improving vascular functions, Ab elimination, energy metabolism, neuronal activity and cognitive function.[3-4] Built on the foundation of previous findings, we investigate whether the TP-MDNP is able enhance early detection of neuroinflammation regardless of Aß or tau expression and evaluate its therapeutic effect in AD mouse model of tauopathy.

METHOD: Three types of transgenic mouse model of AD, TgCRND8+, PS19 with tauopathy, and APP/PS1 were used in the MRI study. The diagnostic performance of Ab-TP-MDNP in MRI was also compared with PET imaging using F18-florobetaben in TgCRND8+ mice. PS19 mice were treated with IV injection of TP-MDNP for two weeks (2/week, 100 μmol Mn/kg b.w.) and the biomarkers for ROS, neuroinflammation, and p-Tau expression were examined using immunohistochemistry and ELISA.

RESULT: Ab-TP-MDNP enhanced MRI signal significantly outperformed PET imaging by Ab-targeted F18-florobetaben in TgCRND8+ mice of 3 months and 6 months of age. Similar MRI imaging sensitivity was observed in PS19 and APP/PS1 mice with or without conjugated antibody against Ab or tau protein, suggesting the neuroinflammation activated MRI contrast enhancement as a common mechanism. In PS19, TP-MDNP treatment significantly reduced total ROS, CA9 (a hypoxia marker) and p-tau levels.

CONCLUSION: The results suggest that TP-MDNP can enable MRI detection of neuroinflammation and reduce neurodegeneration pathogenetic factors such as ROS, hypoxia, and p-tau in AD mouse brains. References 1. Zhang W, et al. Sig Transduct Target Ther 2023;8, 267. 2. He C, et al. Nano Today. 2020;35:100965. 3. Park E,. et al. Advanced Science. 2023 Apr;10(12):2207238. 4. Park E, et al. Biomaterials. 2025 Jan 24:123142.},
}

Animals
*Alzheimer Disease/drug therapy
Mice
Mice, Transgenic
Disease Models, Animal
*Nanoparticles
*Drug Development
Brain/metabolism
Manganese Compounds
Blood-Brain Barrier/metabolism
Humans
Neuroinflammatory Diseases

@article {pmid41449088,
year = {2025},
author = {Addassi, Y and Taylor, H and McDermott, A and Roberts, M and Bennett, B and Jumbo-Lucioni, P},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102447},
doi = {10.1002/alz70859_102447},
pmid = {41449088},
issn = {1552-5279},
mesh = {Animals ; Male ; Female ; *Alzheimer Disease/drug therapy ; Disease Models, Animal ; *Probiotics/therapeutic use/pharmacology ; Humans ; Animals, Genetically Modified ; *Drug Development ; Lactobacillus plantarum ; Amyloid beta-Protein Precursor/genetics/metabolism ; Locomotion/drug effects ; Drosophila ; Drosophila melanogaster ; Memory/drug effects ; },
abstract = {BACKGROUND: Gut microbiota disruptions have been implicated in Alzheimer's disease (AD) pathogenesis. Lactobacillus probiotics have demonstrated therapeutic potential in AD by modulating the gut microbiome, while Lactobacillus postbiotics, soluble factors secreted by live bacteria, confer similar effects with advantages like longer shelf life, lower cost, and reduced infection risk. Evidence of the benefits of postbiotics in AD is limited. This study compares the effectiveness of Lactobacillus probiotics and postbiotics in mitigating behavioral deficits in a Drosophila model of AD.

METHOD: Flies overexpressing human amyloid β precursor protein and β-site APP cleaving enzyme in neurons served as AD model. Lactobacillus plantarum (Lp) was prepared at 1.0 x 10⁹ CFU/µL in MRS Lactobacilli broth, with the upper 80% of culture supernatant filtered as postbiotic fraction (Lp-PBx). Lp and Lp-PBx were diluted 1:2 in 5% sucrose and administered via capillaries in four 24-hour doses over two weeks. Food intake was recorded. Locomotion and memory were assessed at 14 days. Locomotion was evaluated using a negative geotaxis assay testing flies' ability to cross 8-cm in 10 seconds. Memory was tested through an aversive phototaxic suppression assay, where flies were trained to associate light with an aversive odor. After ten training cycles, flies were tested for dark preference. Data was stratified by sex and analyzed through a two-way ANOVA to test the main effects of genotype, treatment, and their interaction.

RESULT: Untreated AD males (0.48±0.03 vs 0.80±0.03, p<0.0001) and females (0.39±0.04 vs 0.70±0.04, p<0.0001) exhibited significant mobility impairments compared to controls. However, AD flies fed Lp or Lp-PBx showed restored mobility, climbing at speeds comparable to controls. Specifically, AD males fed Lp (0.73±0.03) or Lp-PBx (0.75±0.03) and females fed Lp (0.61±0.04) or Lp-PBx (0.59±0.04) climbed significantly faster than untreated counterparts (males: 0.48±0.03, p<0.0001; females: 0.39±0.04, p<0.05). While food intake in females was unaffected, males fed Lp ate significantly less than those given Lp-PBx (p=0.0216), regardless of genotype. Memory assays are ongoing.

CONCLUSION: In summary, our findings suggest Lp-PBx as a viable alternative to Lp for managing mobility deficits in a Drosophila model of AD. Its palatability facilitates administration, making it a practical therapeutic option.},
}

Animals
Male
Female
*Alzheimer Disease/drug therapy
Disease Models, Animal
*Probiotics/therapeutic use/pharmacology
Humans
Animals, Genetically Modified
*Drug Development
Lactobacillus plantarum
Amyloid beta-Protein Precursor/genetics/metabolism
Locomotion/drug effects
Drosophila
Drosophila melanogaster
Memory/drug effects

@article {pmid41449073,
year = {2025},
author = {Xu, P},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102249},
doi = {10.1002/alz70859_102249},
pmid = {41449073},
issn = {1552-5279},
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Drug Development ; Mice ; Disease Models, Animal ; Humans ; Microglia/metabolism/drug effects ; *Brain/metabolism/drug effects ; Amyloid beta-Peptides/metabolism ; Blood-Brain Barrier/metabolism ; },
abstract = {BACKGROUND: Programmed death ligand 1 (PD-L1) plays a pivotal role in modulating neuroinflammation in Alzheimer's disease (AD), and PD-L1 upregulation is widely observed in the brains of AD patients. This dysregulation hinders Aβ plaque clearance and leads to detrimental microglial activation.

METHOD: To regulate the PD-L1 in the brain, we developed a brain-targeted Nano-ERASER system (BTN-PDL1).

RESULT: BTN-PDL1 can effectively cross the BBB, deplete PD-L1 through a Trim21-mediated proteasomal degradation in microglia and astrocytes, and revive their functions, which can subsequently clear toxic Aβ fibrils and attenuate neuroinflammation. Animal behavior assay revealed that BTN-PDL1 stopped the progression of AD and improved learning and cognitive capacity in 5XFAD mouse model.

CONCLUSION: Since protein malfunction and neuroinflammation prevail in many CNS disease conditions, the success of BTN-PDL1 could also be beneficial for the treatment of AD, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, stroke, and traumatic brain injury.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism
*Drug Development
Mice
Disease Models, Animal
Humans
Microglia/metabolism/drug effects
*Brain/metabolism/drug effects
Amyloid beta-Peptides/metabolism
Blood-Brain Barrier/metabolism

@article {pmid41449060,
year = {2025},
author = {Feldman, HH and Villain, N and Frisoni, GB and Dubois, B},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e107831},
doi = {10.1002/alz70859_107831},
pmid = {41449060},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnosis/pathology ; Biomarkers ; *Drug Development ; Risk Assessment ; },
abstract = {BACKGROUND: The widespread availability of biomarkers of Alzheimer's pathology (BAP) opens new diagnostic considerations for those who have not clinically expressed the disease but who are identified as being at increased risk based on their BAP. The International Working Group (IWG) updated their recommendations within a patient-centered nosographic approach that considers clinical evaluation as a cornerstone with attention to risk and resilience factors, patterns of biomarkers, comorbidities, genetics, and other test results (Dubois B, et al. JAMA Neurol 2024). They stratify risk and tie it to a specific clinical patient journey, including the communication of risk, tailored management of modifiable risk factors, counselling, multidomain lifestyle interventions, and treatment research considerations.

METHOD: For these updated IWG recommendations, an evidence review of available literature between July 1, 2020 and March 2024 was undertaken with a variety of biomarker search terms and AD. The search included a review of papers focused on near term and lifetime risks of progression to AD dementia in cognitively unimpaired people with different BAP patterns.

RESULT: These IWG recommendations provide a risk stratification framework for unimpaired individuals with classification into "Asymptomatic At-Risk" and "Presymptomatic". The majority of cognitively unimpaired individuals with BAP, including those with an amyloid or AD pathophysiological biomarker, will not express clinical AD in their lifetime. The Presymptomatic group includes those with fully penetrant monogenic mutations, Down syndrome, or alternatively patterns of positive amyloid biomarker with neocortical tau PET biomarkers that reach the threshold of near certainty of clinical expression of AD. Prioritizing the testing of preventive disease modifying treatments is identified as urgent for this Presymptomatic group. Furthermore, it is expected that this group will expand as new evidence and patterns of biomarkers reach the necessary thresholds for their inclusion. Management plans can be further tailored to this classification framework.

CONCLUSION: This IWG risk stratification classification recommends against diagnosis of AD based on BAP alone without its clinical expression. This AD classification lends itself to a tailored management approach and specific patient journeys for each of its groups.},
}

Humans
*Alzheimer Disease/drug therapy/diagnosis/pathology
Biomarkers
*Drug Development
Risk Assessment

@article {pmid41449057,
year = {2025},
author = {Trotier, AF and Randrianaly, JD and Géraudie, A and Jacquot, S and Piguet, F and Bay, S and Lafaye, P and Delatour, B and , },
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e103908},
doi = {10.1002/alz70859_103908},
pmid = {41449057},
issn = {1552-5279},
mesh = {Animals ; *Alzheimer Disease/drug therapy ; Blood-Brain Barrier/metabolism ; Mice ; *Amyloid beta-Peptides/metabolism/immunology ; *Drug Development ; Disease Models, Animal ; *Single-Domain Antibodies ; Mice, Transgenic ; Brain/metabolism ; Humans ; *Immunotherapy/methods ; Plaque, Amyloid ; },
abstract = {BACKGROUND: Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid-beta (Aβ) peptide accumulation, which forms plaques that trigger inflammation, synaptic loss, and neuronal death. Although monoclonal antibodies (mAbs) targeting Aβ aggregates have shown success in reducing plaques, their effect on cognitive decline is limited, potentially due to the challenge posed by the blood-brain barrier (BBB) and brain structure. Camelid nanobodies (VHHs), due to their small size (15 kDa) and single-domain structure, can more effectively penetrate the BBB, diffuse within the brain, and bind difficult-to-reach epitopes, such as those on Aβ plaques or within the intracellular compartment. To enhance the delivery of anti-Aβ VHHs, two strategies were developed: transient BBB opening and brain in situ production via viral vectors. This study aims to develop and assess two novel immunotherapy approaches using the anti-Aβ VHH R3VQ in an AD mouse model.

METHOD: R3VQ was optimized into monomeric, dimeric, and Fc-conjugated formats. In vivo efficacy was evaluated using APP-PS1-KI mice, which develop both intracellular and extracellular Aβ aggregates. The diffusion of R3VQ was assessed through stereotaxic injections of R3VQ variants into the dorsal hippocampus, followed by histological analysis of brain tissue. To transiently open the BBB, microbubbles and low-intensity pulsed ultrasound (LIPU) were used in combination with intravenous (i/V) R3VQ injections, and brain bioavailability was analyzed four hours post-injection. Additionally, AAVr vectors were used to express monomeric or dimeric R3VQ in the brain, and expression was assessed using qPCR and immunofluorescent staining.

RESULT: In vitro assays confirmed that R3VQ effectively recognizes fibrillar and soluble Aβ, inhibiting fibril formation. In vivo, both monomeric and dimeric R3VQ successfully labeled Aβ deposits and diffused widely in the brain compared to conventional IgGs. Preliminary results from the enhanced immunotherapy strategies show that R3VQ can cross the BBB, bind amyloid plaques, and enter neuronal cells following LIPU-induced BBB opening. AAV delivery of R3VQ resulted in robust astrocytic expression in the brain. Ongoing analyses aim to evaluate the therapeutic potential of these approaches.

CONCLUSION: This study explores innovative passive immunotherapy strategies targeting Aβ, with potential to advance AD treatment and deepen understanding of the disease's pathophysiology.},
}

Animals
*Alzheimer Disease/drug therapy
Blood-Brain Barrier/metabolism
Mice
*Amyloid beta-Peptides/metabolism/immunology
*Drug Development
Disease Models, Animal
*Single-Domain Antibodies
Mice, Transgenic
Brain/metabolism
Humans
*Immunotherapy/methods
Plaque, Amyloid

@article {pmid41448920,
year = {2025},
author = {Dhillon, A},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e101443},
doi = {10.1002/alz70858_101443},
pmid = {41448920},
issn = {1552-5279},
mesh = {Humans ; *Dementia/epidemiology/therapy/psychology ; Prevalence ; *Alzheimer Disease/epidemiology/therapy/psychology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) accounts for 60-70% of dementia cases. Unlike other types, AD is characterized by amyloid plaques and neurofibrillary tangles causing neurodegeneration (Kalaria, 2018; McKeith et al., 2005). The predictable course begins with memory loss and progresses to severe cognitive impairment. With significant social and economic impact, addressing AD's burden in regions like MENA is crucial for effective public health planning and targeted interventions.

METHODS: A comprehensive literature search was conducted using reputable databases, including PubMed and Scopus. The search parameters were refined with specific keywords and Boolean operators to ensure relevance. A multi-step screening process reviewed titles, abstracts, and full texts to collect relevant information on methodology, sample size, interventions, outcomes, and key findings.

RESULTS: Our literature review found that dementia prevalence, including AD, has risen 3% since 1990 to 777.6 per 100,000 people in MENA by 2019. By 2050, 152 million people will live with dementia globally. MENA shows regional variations: Turkey and Bahrain have higher rates than the UAE and Afghanistan. Dementia costs $10.4-13.9 billion annually in MENA, including healthcare expenses and informal care. Healthcare disparities hinder AD diagnosis and treatment in low-income countries like Yemen and Afghanistan due to limited access to diagnostic tools, trained providers, and cultural stigma. In contrast, GCC nations have advanced early diagnosis and care systems. This highlights the need for policies that expand dementia care infrastructure, improve accessibility to diagnostic tools, and train healthcare providers to address AD management demands in under-resourced areas.

CONCLUSION: The MENA region requires urgent attention to understand dementia and AD causes. It is crucial to investigate public and healthcare professionals' understanding and attitudes towards AD, as well as proposed solutions to address gaps in the region. This study aims to fill this knowledge gap. References: 1. Kalaria, R. N. (2018). The pathology and pathophysiology of vascular dementia. Neuropharmacology, 134, 226-239. 2. McKeith, I. G., et al. (2005). Diagnosis and management of dementia with Lewy bodies: Third report of the DLB Consortium. Neurology, 65(12), 1863-1872.},
}

Humans
*Dementia/epidemiology/therapy/psychology
Prevalence
*Alzheimer Disease/epidemiology/therapy/psychology

@article {pmid41448919,
year = {2025},
author = {Wang, P and Weiss, I and Zheng, P and Liu, Y},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e101773},
doi = {10.1002/alz70859_101773},
pmid = {41448919},
issn = {1552-5279},
mesh = {Animals ; Mice, Transgenic ; *Alzheimer Disease/pathology/genetics/metabolism/drug therapy ; Humans ; *Brain/pathology/metabolism ; Amyloid beta-Peptides/metabolism ; Mice ; Microglia/metabolism/pathology ; Disease Models, Animal ; tau Proteins/metabolism ; Plaque, Amyloid/pathology/metabolism ; Neurofibrillary Tangles/pathology/metabolism ; },
abstract = {BACKGROUND: Genome-wide association studies (GWASs) suggested associations between late-onset Alzheimer's Disease (AD) and polymorphisms in several Siglec genes in chromosome 19q13(1,2). In the brain, SIGLEC10 is exclusively and abundantly expressed in microglia. Spatial mRNA analysis from AD brain revealed increased Siglec10 mRNA proximal to Aβ plaques over distant brain tissues. Moreover, SIGLEC10 is progressively elevated in AD tauopathy. However, no data showed causative relationship between SIGLEC10 expression and AD pathogenesis.

METHOD: To examine the potential role for SIGLEC10 in AD pathogenesis, we created a transgenic mice line using human genomic fragment encompassing several SIGLECS including SIGLEC10. The transgene is crossed into mice with targeted deletion of SiglecG, the putative orthologue of human SIGLEC10. The transgenic mice and age-match syngeneic WT control mice were assessed for accumulation of Ab amyloid and pTau neurofilament tangles (NFT) by immunohistochemistry and the contribution of SIGLEC10 is confirmed by using an anti-SIGLEC10 mAb.

RESULT: Flow cytometry of single cell suspension of the brain tissue confirmed the microglia exclusive expression of the human SIGLEC10 among brain cells. Importantly, 9-13 months old SIGLEC10 transgenic mice exhibit marked increase of both NFT (immunostained by anti-phospho-Tau (Ser202, Thr205) antibody AT8) and Aβ plaques (immunostained by anti-beta amyloid Ab1-42 antibody H31L21). To confirm contribution of SIGLEC10 to accumulation both Tau and Aβ pathology, mice were treated with either vehicle or anti-SIGLEC10 antibody for 1 month and compared the accumulation of these protein aggregates in the brain. The results show significant reduction of the pTau aggregates and Aβ plaques by anti-SIGLEC10 mAb.

CONCLUSION: Mice with transgenic expression of unmutated human SIGLEC10 gene cluster in microglia presented with marked increase of both NTF and Aβ plaques at 9 to 13 months. Short-term 4-week anti-Siglec10 treatment significantly reduced both NTF and Aβ plaques in transgenic mice. These data demonstrate a causal relationship between SIGLEC10 and pathogenesis of late onset AD which is not associated with pathogenic mutations in early onset AD, such as APOE4, APP, PS1, PS2 or MAPT. To our knowledge, this is the first mouse model in which a single un-mutated human gene cluster exacerbate both pTau aggregates and Aβ plaques, two critical AD hallmarks.},
}

Animals
Mice, Transgenic
*Alzheimer Disease/pathology/genetics/metabolism/drug therapy
Humans
*Brain/pathology/metabolism
Amyloid beta-Peptides/metabolism
Mice
Microglia/metabolism/pathology
Disease Models, Animal
tau Proteins/metabolism
Plaque, Amyloid/pathology/metabolism
Neurofibrillary Tangles/pathology/metabolism

@article {pmid41448894,
year = {2025},
author = {Kerr, AV and Dossetor, J and Huynh, J and Hwang, YT},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e100668},
doi = {10.1002/alz70858_100668},
pmid = {41448894},
issn = {1552-5279},
mesh = {Humans ; Male ; *Dementia/psychology/drug therapy ; Female ; Surveys and Questionnaires ; Aged ; Middle Aged ; Australia ; Caregivers/psychology ; *Medical Marijuana/therapeutic use ; Adult ; Aged, 80 and over ; Cannabinoids/therapeutic use ; },
abstract = {BACKGROUND: Dementia is a broad term that covers multiple conditions which affect the brain, such as Alzheimer's disease and Frontotemporal dementia. The collection of symptoms caused by these disorders vary and can include disrupted mood, apathy, agitation, aggression, disinhibition, and/or sleep. There has been increasing interest in exploring potential benefits of cannabis-derived medicine in alleviating neuropsychiatric symptoms of dementia. We examined the attitudes towards the use of cannabinoids for symptomatic treatment of dementia among Australian adults diagnosed with different dementia types, their caregivers, and healthy controls.

METHOD: Patients with a diagnosis of dementia, their caregivers, and healthy controls from the FRONTIER research database, at the University of Sydney, completed an online questionnaire assessing attitudes toward medicinal cannabis and cannabinoid use. The questionnaire inquired about the perceived benefits and risks of cannabis use; experience with cannabis use; and interest in participating in a hypothetical clinical trial using medicinal cannabis for the symptomatic treatment of dementia. There were 77 respondents to the questionnaire: 22 dementia patients, 30 study partners, and 25 healthy controls.

RESULT: Of respondents with a diagnosis of dementia, 73% said they would consider participating in a clinical trial exploring the potential therapeutic effects of medicinal cannabis. Out of all participants who completed the survey, 80% said they would consider participating in such a trial. While only 24% of the participants reported previous recreational or medicinal cannabis use, there remains a strong general interest in exploring the potential benefits of cannabinoids through clinical trials.

CONCLUSION: The results from this questionnaire show that there is a strong interest from Australian dementia patients and their caregivers to participate in future clinical trials that would assess the effectiveness of medicinal cannabis in alleviating dementia symptoms. As evidenced by this and other studies, there is growing support for the consideration of cannabis-derived products as medical treatments. We propose that robustly designed clinical trials with clearly defined outcome measures would be of interest and have the potential to expand symptomatic treatment options to those living with dementia.},
}

Humans
Male
*Dementia/psychology/drug therapy
Female
Surveys and Questionnaires
Aged
Middle Aged
Australia
Caregivers/psychology
*Medical Marijuana/therapeutic use
Adult
Aged, 80 and over
Cannabinoids/therapeutic use

@article {pmid41448892,
year = {2025},
author = {Sabbagh, MN and Macfarlane, S and Gabelle, A and Grimmer, T and Jin, K and Chezem, WR and Lopez-Talavera, JC and Missling, CU},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e101346},
doi = {10.1002/alz70859_101346},
pmid = {41448892},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Drug Development ; Male ; Double-Blind Method ; Female ; Aged ; Treatment Outcome ; Administration, Oral ; },
abstract = {BACKGROUND: There are no approved oral disease-modifying small molecule therapies for treatment of early Alzheimer's disease (AD). Blarcamesine is an orally bioavailable small molecule that enhances autophagy through SIGMAR1 activation and restoration of cellular homeostasis in early AD.

METHOD: The ATTENTION-AD study was an up to 144-week open-label extension study subsequent the 48-Week Phase IIb/III double-blind placebo-controlled ANAVEX[®]2-73-AD-004 study, to evaluate the safety and efficacy of oral once daily blarcamesine in 508 participants with early AD. Delayed-start analysis was performed to assess the effect of early treatment initiation up to 192 Weeks.

RESULT: The ATTENTION-AD trial confirmed the good efficacy and safety profile of once daily oral blarcamesine and also demonstrated the manageable nature of the most frequent treatment emergent adverse event (TEAE) (dizziness) observed in the preceding ANAVEX[®]2-73-AD-004 trial, which was generally transient in duration (approx. 7-11 days) and mild or moderate in severity (Grade 1 or 2). The titration schedule was adjusted to a slightly longer titration period in the ATTENTION-AD trial, from previous 2-3 weeks to 10 weeks. A markedly lower frequency of the TEAE of dizziness in the respective maintenance phase was observed: from previously 25.2% in the ANAVEX[®]2-73-AD-004 trial to 9.6% in the ATTENTION-AD trial, demonstrating the manageable nature of this TEAE. No severe or life-threatening adverse events were attributed to blarcamesine. No Amyloid Related Imaging Abnormalities (ARIA) adverse events were identified. There were no deaths related to blarcamesine. Efficacy of the cognitive and functional endpoints in the delayed-start analysis of treatment resulted in significant outcomes, ADAS-Cog13 (LS mean difference -3.83, P = 0.0165) and ADCS-ADL (LS mean difference +4.30, P = 0.0206) at Week 192, reflecting importance of early treatment initiation with oral blarcamesine.

CONCLUSION: Blarcamesine significantly reduced clinical decline showing meaningful benefit for early Alzheimer's disease patients. Blarcamesine exhibited a favorable safety profile with no treatment-related deaths and demonstrated no associated neuroimaging adverse events with continued treatment over 4 years. Altogether, these results indicate that blarcamesine may be an effective, safe, and novel scalable oral treatment for early AD.},
}

Humans
*Alzheimer Disease/drug therapy
*Drug Development
Male
Double-Blind Method
Female
Aged
Treatment Outcome
Administration, Oral

@article {pmid41448891,
year = {2025},
author = {Scharre, DW and Truelove, J and Kovesci, R and Ramamurthy, A and Thurin, K and Middleton, A and Bouchachi, S},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e101678},
doi = {10.1002/alz70858_101678},
pmid = {41448891},
issn = {1552-5279},
mesh = {Humans ; *Dementia/psychology/diagnosis/drug therapy/therapy ; *Cognitive Dysfunction/drug therapy/psychology/diagnosis ; *Alzheimer Disease/drug therapy/psychology ; },
abstract = {Anti-amyloid monoclonal antibodies are approved for use in patients with Mild Cognitive Impairment due to Alzheimer's disease (MCI-AD) or mild AD dementia (ADD). In real world settings, the importance of efficient early-stage identification and careful patient selection, is critical for optimal outcomes and reduction of risks when using anti-amyloid therapies (AAT). We developed, at The Ohio State University, clinical guidelines for prescribing AAT including the identification of appropriate patients, required assessments, treatment, and monitoring. Our guideline selection criteria for appropriate patients require a change in memory or thinking over at least 6 months and a clinical diagnosis of MCI-AD or mild ADD which was operationally defined by specific cognitive assessment score cut offs (SAGE or BrainTest >9, MMSE>19, or MoCA >16), number of cognitive domains impaired (≥1 or ≤4 domains of memory, executive, attention, language, and visuospatial), and functional surveys that require hands-on assistance for one to four instrumental activities of daily living (ADLs) and the ability to perform all basic ADLs. Our guidelines required ruling out other non-Alzheimer's causes of cognitive impairment and verifying amyloid pathology by FDA approved AD biomarkers. Patients were excluded if they were on anticoagulants, unable to have a brain MRI, or with significant psychiatric symptoms making infusions unsafe or impractical. Our guidelines specify every 6-month cognitive and functional assessment monitoring as above with stoppage criteria for ATT including upon progression to moderate ADD stage. After 18 months of therapy, and every 6 months thereafter if they remain on donanemab therapy, our guidelines recommend that amyloid pathology should be reevaluated and if levels are normal, donanemab should be stooped. Lecanemab can be continued until progression to moderate ADD stage. Our guideline includes the FDA prescribing information regarding recommended infusion dosing and timing for lecanemab and donanemab, titration schedule for donanemab, and MRI safety monitoring. We present these clinical guidelines for ATT prescribing as an efficient way to identify appropriate patients and monitor them in real world practice settings. We encourage debate and alternative guidelines that are data-driven following clinical and real-world investigations, with the goal of improving on this guideline we presented.},
}

Humans
*Dementia/psychology/diagnosis/drug therapy/therapy
*Cognitive Dysfunction/drug therapy/psychology/diagnosis
*Alzheimer Disease/drug therapy/psychology

@article {pmid41448888,
year = {2025},
author = {Lee, JK and Lee, J and Shin, J and Lee, EJ and Kim, SW and An, SB and Han, H and Jang, G and Kim, B and Park, S},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e101799},
doi = {10.1002/alz70859_101799},
pmid = {41448888},
issn = {1552-5279},
mesh = {Animals ; Mice ; *Amyloid beta-Peptides/metabolism/immunology ; *Alzheimer Disease/drug therapy/metabolism ; Humans ; *Drug Development ; Microglia/drug effects/metabolism ; Phagocytosis/drug effects ; Disease Models, Animal ; Mice, Transgenic ; Axl Receptor Tyrosine Kinase ; },
abstract = {BACKGROUND: Amyloid-beta (Aβ) accumulation is a hallmark of Alzheimer's disease (AD), and reducing Aβ burden is a key therapeutic strategy. Recent FDA-approved anti-Aβ antibodies, such as Lecanemab and Donanemab, have demonstrated significant reductions in Aβ burden and deceleration of cognitive decline. However, these therapies are associated with adverse events, including antibody-induced neuroinflammation and amyloid-related imaging abnormalities (ARIA). The GAIA platform leverages TAM receptors-Tyro3, Axl and MerTK-to facilitate efferocytosis-driven Aβ clearance without triggering inflammatory responses, addressing limitations of current anti-Aβ immunotherapies. This study evaluates the pharmacokinetic properties and therapeutic efficacy of GAIA-Aβ.

METHOD: GAIA-Aβ was engineered with dual functional domains, a GAS6 domain for TAM receptor binding and Aβ-targeting moiety. Specific binding to oligomeric Aβ (oAβ) and TAM receptors was confirmed using ELISA. TAM receptor-driven phagocytosis and oAβ clearance were evaluated using HMC3, human microglial cell line. Additionally, anti-inflammatory responses were assessed in induced pluripotent stem cell (iPSC)-derived monocytes. Pharmacokinetic properties of GAIA-Aβ were analyzed to determine serum exposure and brain-to-serum ratio. To evaluate the in vivo efficacy, GAIA-Aβ was intravenously administered to 5xFAD mice once weekly (QW) for 8 weeks, and Aβ plaque burden and glial phagocytic activity were assessed using immunohistochemistry.

RESULT: GAIA-Aβ exhibited specific binding to oAβ and activated TAM receptors in a dose-dependent manner. Phagocytosis assays demonstrated effective clearance of oAβ while reducing inflammatory cytokines, indicating successful efferocytosis-mediated activity. Pharmacokinetic analysis revealed that GAIA-Aβ possesses properties comparable to conventional monoclonal antibodies. In 5xFAD mice, GAIA-Aβ treatment led to significant reductions in Aβ plaques and enhanced glial-mediated clearance, particularly via astrocyte engagement.

CONCLUSION: GAIA-Aβ effectively reduces Aβ burden while mitigating neuroinflammation, presenting a favorable safety profile compared to existing anti-Aβ antibodies. These findings highlight the potential of GAIA-Aβ as an improved therapeutic approach for Alzheimer's disease, addressing the limitations of current anti-Aβ immunotherapies.},
}

Animals
Mice
*Amyloid beta-Peptides/metabolism/immunology
*Alzheimer Disease/drug therapy/metabolism
Humans
*Drug Development
Microglia/drug effects/metabolism
Phagocytosis/drug effects
Disease Models, Animal
Mice, Transgenic
Axl Receptor Tyrosine Kinase

@article {pmid41448883,
year = {2025},
author = {Lee, JS and Rhee, HY and Park, KC},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e101851},
doi = {10.1002/alz70859_101851},
pmid = {41448883},
issn = {1552-5279},
mesh = {Humans ; *Cognitive Dysfunction/drug therapy/diet therapy ; Male ; Female ; Double-Blind Method ; Aged ; *Dietary Supplements ; *Drug Development ; *Probiotics/therapeutic use ; Alzheimer Disease ; Neuropsychological Tests ; *Gastrointestinal Microbiome/drug effects ; Middle Aged ; },
abstract = {BACKGROUND: Mild cognitive impairment (MCI) represents the symptomatic pre-dementia stage of Alzheimer's disease (AD). Given the increasing prevalence of AD and its socioeconomic burden, delaying the progression of MCI to AD is critical. Modulating the microbiota-gut-brain (MGB) axis has emerged as a promising therapeutic approach. This study aimed to evaluate the efficacy and safety of MT104, a dietary supplement containing Cuscuta seeds and heat-killed probiotics, in regulating the MGB axis in patients with MCI.

METHOD: This multicenter, randomized, double-blind, placebo-controlled study involved participants randomly assigned in a 1:1 ratio to receive MT104 or placebo. Cognitive function was assessed using the Korean-Montreal Cognitive Assessment (K-MoCA) and Korean-Mini Mental State Examination at baseline and after 12 weeks of treatment. Visuospatial and memory functions were evaluated using the Rey Complex Figure Test and Seoul Verbal Learning Test (SVLT). Statistical analyses included t-tests, Mann-Whitney U tests, analysis of covariance (ANCOVA), and ranked ANCOVA.

RESULT: The mean changes in verbal memory function, as measured by SVLT delayed recall, showed clinically significant improvement in the MT104 group compared with the placebo group in the intention-to-treat and per-protocol groups. The global cognition, as measured by the K-MoCA, also significantly improved in the per-protocol group. Additionally, there were no significant findings regarding the safety profile of MT104.

CONCLUSION: MT104 improved memory performance and global cognition in patients with MCI without safety concerns. These findings support the potential of dietary therapeutic strategies to reduce the risk of progression from MCI to AD dementia. Further studies are needed to confirm these results and explore the long-term benefits of MT104.},
}

Humans
*Cognitive Dysfunction/drug therapy/diet therapy
Male
Female
Double-Blind Method
Aged
*Dietary Supplements
*Drug Development
*Probiotics/therapeutic use
Alzheimer Disease
Neuropsychological Tests
*Gastrointestinal Microbiome/drug effects
Middle Aged

@article {pmid41448874,
year = {2025},
author = {Wu, CY and Chen, L and Arnold, SE and Dodge, HH},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e100939},
doi = {10.1002/alz70859_100939},
pmid = {41448874},
issn = {1552-5279},
mesh = {Humans ; Aged ; Male ; Female ; Single-Blind Method ; *Cognitive Dysfunction/drug therapy/psychology/therapy ; *Drug Development ; Aged, 80 and over ; Neuropsychological Tests ; },
abstract = {BACKGROUND: With U.S. Food and Drug Administration (FDA)-approved anti-amyloid, partially disease-modifying treatments now available, the ethical justification for randomly assigning patients to placebo has become controversial. The idea of twin-controls (or virtual-controls) has gained significant attention in recent years, with the aim of creating twin patient cohorts that can be used as a surrogate to evaluate the effects of treatment on a personalized level. While promising, the feasibility of digital twins techniques remains largely untested.

METHOD: I-CONECT is a multi-site, single-blind, randomized controlled trial (RCT) examining the effects of conversational interactions on cognition among socially isolated subjects aged ≥ 75 years (normal cognition; mild cognitive impairment). 186 participants were randomized into experimental or control groups. The experimental group engaged in video chats with study staff 4 times/week for 6 months, while the control groups received weekly 10-minute phone calls. The current analysis focused on the efficacy-shown Montreal Cognitive Assessment (MoCA; global cognition) and category fluency animals (CFA; language-based executive function) at 6-month follow-up. Data from the National Alzheimer's Coordinating Center-Uniform Data Set (NACC-UDS) were used to create digital twins for treatment participants through two methods. Method 1 involved twin mapping, matching participants with 1 to 20 twins who had similar demographic, biological, and social factors, and comparing change scores between each participant and their twins. Method 2 used direct modeling by building random forest models to predict change scores as if participants were assigned to a "usual care" control group. Effect sizes were compared between original and twin-controls trials, as well as between the two methods.

RESULT: Approximately 10% of NACC-UDS participants (5,332 out of 50,259) were eligible for I-CONECT. For parallel-group designs, treatment effect sizes on MoCA closely aligned between original (β=1.67) and twin-control (β=1.46-1.97) trials when the Euclidean distance mapping was applied. Similar findings were found in CFA (original trial β=2.56; twin-control trial β=2.31-3.34). For single-case, n-of-1 designs, methods 1 and 2 showed substantial agreement in identifying treatment responders (Cohen's Kappa=1 for MoCA; 0.68 for CFA).

CONCLUSION: Digital twins from publicly available datasets enhance the rigor of RCTs by providing mapped twins as controls for early-phase dementia trials.},
}

Humans
Aged
Male
Female
Single-Blind Method
*Cognitive Dysfunction/drug therapy/psychology/therapy
*Drug Development
Aged, 80 and over
Neuropsychological Tests

@article {pmid41448861,
year = {2025},
author = {Zuchero, J},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102246},
doi = {10.1002/alz70859_102246},
pmid = {41448861},
issn = {1552-5279},
mesh = {Animals ; *Amyloid beta-Peptides/immunology/metabolism ; *Alzheimer Disease/drug therapy/pathology ; Mice ; *Drug Development ; *Brain/metabolism/drug effects/pathology ; Disease Models, Animal ; *Receptors, Transferrin/metabolism/immunology ; Plaque, Amyloid/pathology ; Humans ; },
abstract = {BACKGROUND: Although the first generation of immunotherapies for Alzheimer's disease (AD) are now clinically approved, amyloid-related imaging abnormalities (ARIA) remain a major safety problem for this class of drugs.

METHOD: Here, we report an antibody transport vehicle (ATV) targeting the transferrin receptor (TfR) for brain delivery of amyloid beta (Aβ) antibodies that significantly reduced ARIA-like lesions and improved plaque target engagement in a mouse model of amyloid deposition.

RESULT: Asymmetrical Fc mutations (ATVcisLALA) allowed the molecule to selectively retain effector function only when bound to Aβ while mitigating TfR-related hematology liabilities. Mice treated with ATVcisLALA:Aβ exhibited broad brain parenchymal antibody distribution; in contrast, anti-Aβ IgG was highly localized to arterial perivascular spaces where vascular Aβ accumulates and likely plays a role in induction of ARIA. Importantly, ATVcisLALA: Aβ almost completely eliminated ARIA-like lesions and vascular inflammation associated with anti-Aβ treatment.

CONCLUSION: Taken together, ATVcisLALA has the potential to significantly improve both safety and efficacy of Aβ immunotherapy through enhanced biodistribution mediated by transport across the blood-brain barrier.},
}

Animals
*Amyloid beta-Peptides/immunology/metabolism
*Alzheimer Disease/drug therapy/pathology
Mice
*Drug Development
*Brain/metabolism/drug effects/pathology
Disease Models, Animal
*Receptors, Transferrin/metabolism/immunology
Plaque, Amyloid/pathology
Humans

@article {pmid41448849,
year = {2025},
author = {Ishii, K and Yamada, T and Hanaoka, K and Kaida, H and Kimura, Y},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e102438},
doi = {10.1002/alz70856_102438},
pmid = {41448849},
issn = {1552-5279},
mesh = {Humans ; *Positron-Emission Tomography ; Male ; Female ; Fluorodeoxyglucose F18 ; Aged ; *Brain/diagnostic imaging/metabolism ; Magnetic Resonance Imaging ; Biomarkers/metabolism ; *Alzheimer Disease/diagnostic imaging/metabolism ; Radiopharmaceuticals ; Aniline Compounds ; Algorithms ; Thiazoles ; Support Vector Machine ; Middle Aged ; Aged, 80 and over ; Amyloid/metabolism ; },
abstract = {BACKGROUND: Since the approval of disease-modifying drugs for Alzheimer's disease, the demand for amyloid positron emission tomography (PET) scans, which are crucial for determining treatment eligibility, is expected to increase significantly. We thus investigated the ability of an algorithm to predict amyloid accumulation from [18]F-fluorodeoxyglucose (FDG)-PET images for use in amyloid PET screening.

METHOD: We analyzed the images of 194 subjects with cognitive disorders who had undergone brain FDG-PET, amyloid PET using Pittsburgh compound-B ([11]C-PiB), and MRI scans at Kindai University Hospital between 2011 and 2018. Among them, 108 subjects showed positive amyloid accumulation; the other 86 did not. For the 108 positive cases, the input values were the region of interest-based calculated from the automatic anatomical labeling template, which divides the brain into 120 regions, applied to the anatomically standardized FDG-PET images of each subject. We then used a support-vector machine (SVM) machine learning algorithm and conducted a 10-fold cross-validation to assess the algorithm's accuracy for predicting amyloid accumulation from FDG-PET images.

RESULT: We observed 81.5% accuracy, 78.5% sensitivity, 84.6% specificity, and an area under the curve (AUC) of 0.846 during training. The validation results for the trained model revealed 85.9% accuracy, 88.4% sensitivity, 81.0% specificity, and an AUC of 0.918.

CONCLUSION: The performance of our algorithm to predict amyloid accumulation in subjects with cognitive disorders from [18]FDG-PET images is adequate for use in amyloid PET scan screenings.},
}

Humans
*Positron-Emission Tomography
Male
Female
Fluorodeoxyglucose F18
Aged
*Brain/diagnostic imaging/metabolism
Magnetic Resonance Imaging
Biomarkers/metabolism
*Alzheimer Disease/diagnostic imaging/metabolism
Radiopharmaceuticals
Aniline Compounds
Algorithms
Thiazoles
Support Vector Machine
Middle Aged
Aged, 80 and over
Amyloid/metabolism

@article {pmid41448844,
year = {2025},
author = {Zhang, W and Chen, M and Tian, Q and Yu, W and Lü, Y},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102585},
doi = {10.1002/alz70859_102585},
pmid = {41448844},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Spectroscopy, Near-Infrared ; Male ; Female ; Aged ; *Drug Development ; *Brain/drug effects/diagnostic imaging ; Neuropsychological Tests ; Amyloid beta-Peptides ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Middle Aged ; },
abstract = {BACKGROUND: Lecanemab, a monoclonal antibody targeting amyloid-beta (Aβ) aggregates, has shown efficacy in reducing Aβ burden in Alzheimer's disease (AD). However, its impact on brain function remains understudied. We employed functional near-infrared spectroscopy (fNIRS) during the Clock Drawing Test (CDT) to examine potential changes in brain function following lecanemab treatment.

METHOD: Three patients with clinically diagnosed AD were recruited from the Memory Clinic of The First Affiliated Hospital of Chongqing Medical University. Each patient underwent fNIRS assessments during a CDT paradigm (task + 20 s rest blocks) at baseline and after 12 weeks of lecanemab therapy. Hemodynamic responses were analyzed using a generalized linear model (GLM) to extract β1 values. We further assessed functional connectivity (FC) among predefined regions of interest (ROIs). A paired t-test was conducted to compare CDT performance (15-point CLOX system) and fNIRS-derived metrics before and after treatment.

RESULT: Two patients reported no adverse events; one experienced a mild headache following the first infusion. CDT scores did not show a statistically significant improvement after 12 weeks (p = 0.157). In contrast, fNIRS data revealed a significant increase in β1 values at channel 15 (right primary somatosensory cortex) (p < 0.05, FDR corrected). ROI-based FC analysis demonstrated enhanced connectivity between the right frontal (F.R) and left occipital (O.L) regions, as well as between the right parietal (P.R) and right occipital (O.R) regions (both p < 0.05, FDR corrected). Conversely, FC between the left frontal (F.L) and right parietal (P.R) regions decreased (p < 0.05, FDR corrected).

CONCLUSION: Lecanemab therapy may induce notable changes in brain functional connectivity and neural activation patterns in AD, as evidenced by fNIRS during the CDT. The observed increase in frontal-occipital FC may indicate improved network coordination, whereas the decreased parietal-frontal connectivity could reflect compensatory reorganization. These findings underscore the potential of fNIRS for monitoring treatment-related neuronal changes in AD and warrant validation in larger cohorts.},
}

Humans
*Alzheimer Disease/drug therapy
Spectroscopy, Near-Infrared
Male
Female
Aged
*Drug Development
*Brain/drug effects/diagnostic imaging
Neuropsychological Tests
Amyloid beta-Peptides
*Antibodies, Monoclonal, Humanized/therapeutic use
Middle Aged

@article {pmid41448839,
year = {2025},
author = {McCain, S and Reader, JM and Roberts, JS},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e107068},
doi = {10.1002/alz70858_107068},
pmid = {41448839},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; Cross-Sectional Studies ; Middle Aged ; *Alzheimer Disease/psychology/therapy ; Surveys and Questionnaires ; *Optimism/psychology ; Aged, 80 and over ; United States ; *Dementia/psychology/therapy ; },
abstract = {BACKGROUND: The health psychology literature suggests that treatment optimism (i.e., the belief that disease-specific treatments' efficacy and availability will significantly improve over time) may predict help-seeking and influence medical decisions (e.g., disease screening and early detection). However, little is known about treatment optimism regarding Alzheimer's disease (AD). This secondary data analysis describes AD treatment optimism and its predictors among a nationally representative sample of older adults in the US.

METHOD: The National Poll on Healthy Aging (NPHA), a recurring, nationally representative survey of adults aged 50 and older, conducted a cross-sectional internet and telephone survey in 2023 using NORC's AmeriSpeak Panel®. Survey measures included self-reported demographic/health characteristics (e.g., family history of AD) and dementia-related perceptions (e.g., concern about developing AD, subjective memory rating). The main outcome measure assessed AD treatment optimism by asking respondents to rate their agreement (1=Strongly Disagree to 5=Strongly Disagree) with the statement: "AD will one day become a manageable chronic condition like diabetes or heart disease." Logistic regression modeling identified predictors of treatment optimism, utilizing a significance value of p <0.05.

RESULT: The sample included 1,292 respondents, with a mean age of 70.9 years (range: 50-80; SD: 7.89) and a majority reporting as female (52.0%) and non-Hispanic white (58.1%) (Table 1). Most (52.9%) respondents agreed that AD would one day become a manageable condition, with 10.3% strongly agreeing. AD treatment optimism was associated with older age (OR: 1.05; 95% CI: 1.018, 1.077), self-reported good to excellent general health (OR: 1.38; 95% CI: 1.003, 1.912), and household income <$30,000 ($30,000-$60,000: OR: 0.71, 95% CI: 0.506, 0.984; >$100,000: OR: 0.63, 95% CI: 0.426, 0.918) (Table 2). AD treatment optimism did not differ significantly by gender, race/ethnicity, education, mental health, family history of AD, concern about developing AD, or subjective memory rating.

CONCLUSION: Findings from this nationally representative survey suggest high overall levels of treatment optimism among US older adults, with treatment optimism significantly differing by age, health status, and household income. Future research is needed to determine how older adults' treatment optimism changes in the face of improved therapies and influences their engagement in emerging AD screening and therapeutic options.},
}

Humans
Female
Male
Aged
Cross-Sectional Studies
Middle Aged
*Alzheimer Disease/psychology/therapy
Surveys and Questionnaires
*Optimism/psychology
Aged, 80 and over
United States
*Dementia/psychology/therapy

@article {pmid41448835,
year = {2025},
author = {Willbold, D and Kutzsche, J and Cosma, NC and Kauselmann, G and Jürgens, D and Peters, O},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e101508},
doi = {10.1002/alz70859_101508},
pmid = {41448835},
issn = {1552-5279},
mesh = {Humans ; Male ; *Alzheimer Disease/drug therapy ; Female ; *Cognitive Dysfunction/drug therapy ; Double-Blind Method ; Aged ; Amyloid beta-Peptides/cerebrospinal fluid ; *Drug Development ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Self-replicating amyloid beta (Aβ) oligomers are described to be synaptotoxic and responsible for reduced synaptic plasticity, impaired neuronal function and thus for development and progression of Alzheimer's disease (AD). The all-D-enantiomeric peptide PRI-002 was developed to disassemble toxic Aβ oligomers into harmless Aβ monomers, very similar to a chaperone. PRI-002 is expected to reduce neurotoxicity and to restore synaptic plasticity in early AD stages. Target engagement has been demonstrated in vitro, in vivo and ex vivo. PRI-002 has previously been shown to reverse cognition deficits in four different animal models in four different laboratories. PRI-002 has also demonstrated to be safe and well tolerable in healthy volunteers. Here we aim to demonstrate safety in patients with mild cognitive impairment (MCI) and mild dementia due to AD and to explore efficacy.

METHOD: We carried out a randomized, placebo-controlled, double-blind, Phase 1b study to evaluate safety, tolerability and pharmacodynamics of PRI-002 in 20 patients with MCI to mild dementia due to AD. Eligible patients were blindly randomly assigned (1:1) to receive 300 mg PRI-002 per day or placebo for 28 days. Follow-up assessment took place on day 56. The trial is registered in EudraCT 2020-003416-27.

RESULT: 19 out of 20 patients were randomly assigned to PRI-002 (n=9) or placebo (n=10) and completed the study per protocol. PRI-002 was well tolerated. No SAEs were reported. Clinically meaningful findings were not reported. ECG, EEG and MRI revealed no changes. As expected, no ARIA were observed. No significant changes were detected in p-tau, t-tau, Aβ 1-40, Aβ 1-42 and Aβ oligomers in CSF. In contrast to patients in the placebo group, each of the patients in the verum group had increased short-term-memory abilities as demonstrated in the CERAD word list at day 56 vs. baseline (p<0.01).

CONCLUSION: PRI-002 was well tolerated. No biomarker changes have been found after 28 days of treatment. No ARIA were detected. Memory improved significantly in the verum group. The randomized, double-blind, placebo-controlled PRImus-AD phase 2 study has finished recruiting to assess safety and efficacy of PRI-002 in patients with MCI and mild dementia due to AD (EU CT# 2022-503148-41).},
}

Humans
Male
*Alzheimer Disease/drug therapy
Female
*Cognitive Dysfunction/drug therapy
Double-Blind Method
Aged
Amyloid beta-Peptides/cerebrospinal fluid
*Drug Development
Middle Aged
Aged, 80 and over

@article {pmid41448825,
year = {2025},
author = {Shigematsu, K and Komori, N and Yamagishi, H},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102343},
doi = {10.1002/alz70859_102343},
pmid = {41448825},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; Prospective Studies ; *Hand Strength/physiology ; Aged, 80 and over ; *Mesenchymal Stem Cell Transplantation/methods ; *Drug Development ; Parkinson Disease/therapy ; Alzheimer Disease/therapy ; *Cholinesterases/blood ; Amyotrophic Lateral Sclerosis/therapy ; Supranuclear Palsy, Progressive/therapy ; },
abstract = {BACKGROUND: Immediate improvements in subjective and objective symptoms can sometimes be observed following the administration of adipose-derived mesenchymal stem cells (ADSCs). This rapid improvement was surprising, as we had assumed that regenerative medicine would require several days or more to show effects. Therefore, we measured grip strength and cholinesterase values before and after treatment. ADSCs have gained attention in regenerative medicine due to their multipotent nature and potential therapeutic effects.

METHOD: We conducted a prospective observational study on 21 patients who received ADSC treatment. Informed consent was obtained from all participants. Serum cholinesterase levels and grip strength were measured immediately before and after ADSC administration. Grip strength was measured on the non-infusion side, maintaining the same posture for both pre- and post-treatment measurements.

RESULT: The study included patients with various conditions: Parkinson's disease (PD, n=9), Amyotrophic Lateral Sclerosis (ALS, n=4), Alzheimer's disease (n=2), Chronic Obstructive Pulmonary Disease (COPD, n=4), and Progressive Supranuclear Palsy (PSP, n=1). The mean age was 67.5 years (range: 53-81), with 14 males and 7 females. A paired samples t-test revealed a statistically significant decrease in cholinesterase levels after ADSC administration (mean difference: -21.905 U/L, p < 0.001). Although not statistically significant, there was a trend towards improvement in grip strength (mean difference: 1.0619 kg, p = 0.119).

CONCLUSION: Our findings demonstrate a significant immediate decrease in serum cholinesterase levels following ADSC administration. The observed decrease in cholinesterase levels might indicate an enhancement of acetylcholine activity, potentially explaining the trend towards improved grip strength. The immediate effects observed in this study are intriguing, as they suggest that ADSCs may have rapid neuromodulatory effects beyond their known regenerative properties. Previous studies have shown that ADSCs can differentiate into various cell types, including neural cells, and secrete neurotrophic factors. The trend towards improved grip strength, although not statistically significant, is noteworthy. Grip strength is a reliable indicator of overall muscle strength and has been associated with various health outcomes. The potential improvement in grip strength immediately after ADSC administration warrants further investigation, as it could have implications for patients with neuromuscular disorders.},
}

Humans
Male
Female
Aged
Middle Aged
Prospective Studies
*Hand Strength/physiology
Aged, 80 and over
*Mesenchymal Stem Cell Transplantation/methods
*Drug Development
Parkinson Disease/therapy
Alzheimer Disease/therapy
*Cholinesterases/blood
Amyotrophic Lateral Sclerosis/therapy
Supranuclear Palsy, Progressive/therapy

@article {pmid41448824,
year = {2025},
author = {Weigand, AJ and Brailow, TR and Jarrott, S and Atkins, KJ and Reck-Rivera, C and Tsoy, E and Possin, KL},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e104681},
doi = {10.1002/alz70857_104681},
pmid = {41448824},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; Psychometrics ; Reproducibility of Results ; *Dementia/diagnosis ; Aged, 80 and over ; Severity of Illness Index ; *Mental Status and Dementia Tests ; *Alzheimer Disease/diagnosis ; Neuropsychological Tests ; ROC Curve ; },
abstract = {BACKGROUND: There is a need for brief and scalable measures of dementia severity to determine treatment eligibility and inform clinical decision-making. We assessed the psychometric properties and optimal cutoff scores of the Quick Dementia Rating Scale (QDRS) to predict Clinical Dementia Rating Scale (CDR) stages in a large, well-characterized, and clinically diverse sample of older adults with and without neurodegenerative conditions.

METHOD: The 10-item informant-reported QDRS was obtained for 902 participants through the University of California San Francisco Alzheimer's Disease Research Center, 610 of whom had concurrent CDR data and 36 of whom had repeat QDRS data within 6 months. We assessed optimal cut-points based on our sample using receiver operating characteristic (ROC) analyses including bootstrapped comparison of area under the curve (AUC) against previously published QDRS cut-points that were based on 267 participants. Reliability (internal, test-retest) and validity (criterion, convergent, divergent) of the QDRS were also assessed.

RESULT: The QDRS correlated strongly with the CDR sum of boxes (ρ = .87, p < .001, Figure 1) and significantly differed across CDR stages (F = 548.0, p < .001, Figure 2). It also had strong internal reliability (Cronbach's alpha = .94) and acceptable test-retest reliability (ρ = .57). Our optimal cut-point replicated the published cutoff of 1.5 (AUC = .92, Figure 3) to differentiate CDR 0 vs. 0.5 (AUC = .85). When differentiating CDR 0.5 vs. 1, our optimal cutoff was slightly higher (7.5 with AUC = .90 vs. 6.0 with AUC = .84) although when we limited out CDR 1 sample to individuals with an Alzheimer's disease clinical syndrome, a more similar cut-point of 6.5 was found (AUC = .91, Figure 3). Recommendations for adjusting the cut-point for less typical neurodegenerative presentations (e.g., linguistic, behavioral, motor predominant) will be presented at AAIC 2025.

CONCLUSION: The QDRS offers an efficient and scalable measure of dementia severity that can be used as a reliable and valid clinical alternative to the CDR, including for potential determination of eligibility and clinical monitoring for emerging AD treatments.},
}

Humans
Female
Male
Aged
Psychometrics
Reproducibility of Results
*Dementia/diagnosis
Aged, 80 and over
Severity of Illness Index
*Mental Status and Dementia Tests
*Alzheimer Disease/diagnosis
Neuropsychological Tests
ROC Curve

@article {pmid41448821,
year = {2025},
author = {Zhou, H and Shobo, A and Hancock, M and Ansari, FE and Touj, S and Malvankar, M and Wu, PY and Masson, LC and Choquette, T and Chakravarty, MM and McKinney, RA and Multhaup, G},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e101967},
doi = {10.1002/alz70859_101967},
pmid = {41448821},
issn = {1552-5279},
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Mice ; *Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; *Drug Development ; Disease Models, Animal ; *Brain/metabolism/pathology/drug effects ; Male ; Plaque, Amyloid/pathology ; Female ; Peptide Fragments/metabolism ; Humans ; },
abstract = {BACKGROUND: Over the past decade, the Multhaup lab have evaluated the safety and efficacy of a protease resistant D-amino acid Aβ-Interacting Peptide (D-AIP) as a novel anti-amyloid preventive strategy, which targets Aβ accumulation as the primary event in Alzheimer disease (AD) pathogenesis. D-AIP selectively binds to soluble oligomers of Aβ42 in vitro (Barucker et al. 2015), neutralizes Aβ42 oligomer toxicity in Drospohila models (Zhong et al. 2019), and crosses the blood-brain barrier in wild-type mice (Shobo et al. 2022). Here, we investigated effects of D-AIP on early Aβ pathogenesis in 3xTg-AD mice.

METHOD: 3xTg mice were orally treated with D-AIP from 4 to 6-months-old. Liquid chromatography mass spectrometry was used to detect and quantify D-AIP in brain homogenates and plasma. D-AIP and Aβ42 oligomers were localized in 3xTg brains by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). Immunohistochemistry was used to track amyloid pathology, microglia and astrocyte reactivity in brain sections. An ultrasensitive Meso Scale Discovery immunoassay was used to quantify Aβ species and follow the progression of amyloid deposition.

RESULT: Orally dosed D-AIP possessed favourable biostability, pharmacokinetics, and brain region distribution. Notably, (i) D-AIP forms heteromeric complexes with toxic Aβ oligomers in the brains of 3xTg-AD animals, (ii) attenuated plaque amyloid pathology and (iii) attenuated neuroinflammation at the lag-phase of amyloid aggregation in male and female 3xTg mice. Additionally, behaviour and structural analysis showed that D-AIP treatment had no adverse effects on memory and cognition.

CONCLUSION: Our findings demonstrate that oral administrated D-AIP effectively targeted Aβ oligomers to prevent AD-associated deposition and neurotoxicity in an AD mouse model at very early stages of amyloid deposition. Since orally delivered D-AIP had no observable adverse effect it presents great promise as a next-generation AD therapeutic.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism
Mice
*Amyloid beta-Peptides/metabolism
Mice, Transgenic
*Drug Development
Disease Models, Animal
*Brain/metabolism/pathology/drug effects
Male
Plaque, Amyloid/pathology
Female
Peptide Fragments/metabolism
Humans

@article {pmid41448820,
year = {2025},
author = {Turri, M and Aubin, M and Hamilton, LK and Vachon, A and Aumont, A and Plourde, M and Fernandes, KJ},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e100935},
doi = {10.1002/alz70859_100935},
pmid = {41448820},
issn = {1552-5279},
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/metabolism ; Mice ; *Hippocampus/metabolism/drug effects/pathology ; Mice, Transgenic ; Disease Models, Animal ; Male ; Female ; *Drug Development ; *Stearoyl-CoA Desaturase/antagonists & inhibitors ; *Lipid Metabolism/drug effects ; Fatty Acids/metabolism ; Humans ; },
abstract = {BACKGROUND: Alterations in brain lipids are a central feature of Alzheimer's disease (AD), nevertheless therapeutic strategies targeting brain lipid metabolism are still lacking. Our lab recently reported that a pharmacological inhibitor of the fatty acid enzyme, stearoyl-CoA desaturase (SCD), led to recovery of hippocampal synapses with associated improvements in learning and memory in the slow-progressing 3xTg-AD mouse model. Here, we used the 5xFAD rapidly progressing AD model to further delve into lipid metabolism disruptions in AD, and into the effect of the SCD inhibitor (SCDi) on fatty acid (FA) alterations and synapse loss.

METHOD: Hippocampi from 5xFAD and non-carrier control mice were collected at 5 and 8 months old (MO) for FA profiling by gas chromatography-flame ion detection (GC-FID) and for IHC for b-amyloid, GFAP (astrocytes) and Iba-1 (microglia). SCDi or vehicle was infused via intracerebroventricular osmotic pumps for 28 days in 5 MO 5xFAD and NC mice, and their hippocampi were processed for GC-FID and Golgi staining for dendritic spine quantification.

RESULT: FA alterations were apparent in female hippocampus at 5 MO (together with plaque pathology and gliosis) and worsened by the age at 8 MO, while males first showed FA alterations at 8MO (Figure 1). The C16:1/C16:0 desaturation index, parameter associated to SCD enzymatic activity, showed a significant increase in 5xFAD mice at 8 MO, but starting at 5MO in females. Treating 5xFAD females' mice with SCDi improved dendritic spine density and normalized FA levels (Figures 2 and 3).

CONCLUSION: These data demonstrate that SCD inhibitor treatment in a second AD mouse model, the more aggressive 5xFAD model, has beneficial effects on FA alterations and hippocampal dendritic spines. These findings add to accumulating data supporting SCD inhibition as a promising novel therapeutic target for AD.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/metabolism
Mice
*Hippocampus/metabolism/drug effects/pathology
Mice, Transgenic
Disease Models, Animal
Male
Female
*Drug Development
*Stearoyl-CoA Desaturase/antagonists & inhibitors
*Lipid Metabolism/drug effects
Fatty Acids/metabolism
Humans

@article {pmid41448817,
year = {2025},
author = {Zhao, H and Tang, L and Yang, D and Chen, N and Xu, Y},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e101524},
doi = {10.1002/alz70859_101524},
pmid = {41448817},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Prospective Studies ; *Antibodies, Monoclonal, Humanized/therapeutic use ; *Drug Development ; China ; Male ; Female ; *Cognitive Dysfunction/drug therapy ; Amyloid beta-Peptides ; Biomarkers/blood ; Aged ; },
abstract = {BACKGROUND: Lecanemab, a humanized IgG1 monoclonal antibody that targets soluble aggregated Aβ species (protofibrils), has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in early Alzheimer's disease(AD) and received its approval for this indication in the USA 2023 and China 2024. However, reports published of real-world data on this therapy are still very limited, espcially in China. LEAD is an investigator- led, multicenter, prospective, real-world study in 20 hospitals in Jiangsu Province, China. The primary objective was to assess the effectiveness of lecanemab under real-world clinical practice in early Alzheimer's diseasepatients in China. The secondary objectives included evaluating the safety of lecanemab in Chinese patients.

METHOD: This prospective cohort trial included early AD (mild cognitive impairment or mild dementia due to AD) patients having an indication for lecanemab. Each participant had evidence of amyloid on positronemission tomography (PET) or by cerebrospinal fluid testing. Baseline data on demographics, medical history, cognitive score, plasma biomarkers, Apoe and MR indicators were assessed and a treatment with intravenous lecanemab (10 mg per kilogram of body weight each 2 weeks) was started. The patients will be followed up, attend safety visits, provide blood samples to measure AD biomarkers at months 3, 6 and 12. AD blood biomarkers was detected using chemiluminescence. All cognitive assessments will be repeated at month 6 and 12, structural MR will be noted at month 1,1.5,3.5 and 6. The last study visit will be at month 12, when all baseline measurements will be repeated. The study was approved by the Drum Tower Hospital Research Ethics Committee (2024-746-01).

RESULT: This study is onging, 90 subjects have been recruited. Currently in the data extraction phase. Baseline data collection of the subjects is shown in Table 1. All patients will complete 6 months of treatment in July 2025. Updated result will be available for the conference.

CONCLUSION: The LEAD project is a multi-center, real-world study that will determine the therapeutic efficacy of lecanemab in alleviating clinical symptoms and pathological aspects in Alzheimer's disease patients in Jiangsu, China, as well as monitor adverse effects, in order to assist the treatment of more Asian AD patients.},
}

Humans
*Alzheimer Disease/drug therapy
Prospective Studies
*Antibodies, Monoclonal, Humanized/therapeutic use
*Drug Development
China
Male
Female
*Cognitive Dysfunction/drug therapy
Amyloid beta-Peptides
Biomarkers/blood
Aged

@article {pmid41448814,
year = {2025},
author = {Koerich, S and Ramirez, S and Astudillo, N and Colpo, GD and Soto, C},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e100925},
doi = {10.1002/alz70859_100925},
pmid = {41448814},
issn = {1552-5279},
mesh = {Animals ; Mice ; *Alzheimer Disease/pathology/therapy ; *Plaque, Amyloid/pathology/metabolism ; Amyloid beta-Peptides/metabolism ; Mice, Transgenic ; *Drug Development ; Disease Models, Animal ; *Brain/pathology/metabolism ; Amyloid beta-Protein Precursor/genetics ; Male ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia, marked by the accumulation of extracellular amyloid plaques, intraneuronal neurofibrillary tangles, and neuroinflammation, all contributing to cognitive decline. Although disease-modifying therapies targeting amyloid plaques show promise, eligibility for these treatments is limited, and studies suggest that the risks may outweigh the potential benefits for many patients. Recent preclinical studies suggest that peripheral approaches may influence amyloid (Aβ) and tau deposition, as well as neuroinflammation in the brain. Plasma exchange (PE), where plasma is replaced with albumin, has emerged as a potential treatment for AD. This study investigates the effects of PE on Aβ pathology and neuroinflammation in APP/PS1 mice at an advanced stage of amyloid pathology.

METHODS: Four PE procedures were performed monthly starting at 11 months of age. At 15 months, all animals were euthanized, and brains were processed for histological analysis. Amyloid deposits were assessed with Thioflavin-S (ThS) and 4G8 immunostaining in the cortex and hippocampus. ELISA was used to measure soluble and insoluble Aβ1-40 and Aβ1-42 in brain homogenates and plasma. Inflammatory responses were quantified using a Luminex bead-based immunoassay for cytokines (IL-1β, IL-6, TNFα, IFN-γ, IL-10, IL-4) in whole-brain homogenates and plasma. Iba-1 and GFAP immunostaining assessed microglial and astrocyte areas.

RESULTS: PE-treated animals showed significant reductions in amyloid plaque number and area in the cortex compared to untreated APP/PS1 mice. Additionally, Iba-1+ and GFAP+ areas were significantly smaller in PE-treated animals. Biochemical analysis confirmed reductions in insoluble Aβ1-40 and Aβ1-42 levels in the brain of PE-treated animals. PE also modulated the inflammatory response, decreasing IL-1β, IL-6, IL-10, and IL-4 in the brain compared to untreated mice.

CONCLUSIONS: These findings suggest that PE may reduce amyloid burden and modulate inflammation in the brain. An increase in plasma Aβ1-40 and Aβ1-42 after PE suggests Aβ movement from the brain to the blood. Further studies are needed to elucidate the mechanisms underlying Aβ clearance and inflammation modulation.},
}

Animals
Mice
*Alzheimer Disease/pathology/therapy
*Plaque, Amyloid/pathology/metabolism
Amyloid beta-Peptides/metabolism
Mice, Transgenic
*Drug Development
Disease Models, Animal
*Brain/pathology/metabolism
Amyloid beta-Protein Precursor/genetics
Male

@article {pmid41448813,
year = {2025},
author = {Hwang, TJ and Yang, CH and Lin, YT},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e104077},
doi = {10.1002/alz70857_104077},
pmid = {41448813},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Cognitive Dysfunction/diagnosis/psychology ; Aged ; Neuropsychological Tests ; Middle Aged ; Aged, 80 and over ; Psychiatric Status Rating Scales ; Checklist ; Mental Status and Dementia Tests ; },
abstract = {BACKGROUND: Neuropsychiatric symptoms have been considered a risk factor or prodromal state of cognitive decline and further progression into dementia. The Mild Behavioral Impairment Checklist (MBI-C) is a newly developed instrument for assessing the presence and severity of neuropsychiatric changes. However, ratings may be susceptible to biases and discrepancies across different information sources.

METHOD: We recruited participants who did not meet the diagnostic criteria for dementia or other major psychiatric illnesses from both family members of patients and hospital volunteers at the psychiatry department of a university medical center. All participants underwent clinical and cognitive evaluation using the CDR and MMSE and were subsequently classified as either cognitively normal or mild cognitive impairment (MCI). Then, each study participant, informant, and researcher completed the respective version of MBI-C. The researcher's evaluation was based on information collected from the participant and close informant, so it could be considered the gold standard. The MBI criteria outlined by the International Society to Advance Alzheimer's Research and Treatment (ISTAART) was applied to identify participants with MBI. Data were analyzed to examine the differences in MBI-C rating among the three groups.

RESULT: A total of 123 participants with MBI (mean age of 66.8 years, 49 with pure MBI, 74 with MBI and MCI) were identified. Significant differences in 3 domain scores (decreased motivation, affective dysregulation, and social inappropriateness) were observed across the three groups. In the decreased motivation domain, both the self and researcher rating yielded significantly higher scores than the informant one (p < 0.001), with average scores ranging from 1.95 (self-rating) to 1.09 (informant rating). In the affective dysregulation domain, the researcher rating scored significantly higher than the informant rating, with mean scores of 2.57 and 1.9, respectively (p = 0.019). However, within the social inappropriateness domain, the informant rating yielded significantly higher scores than the self-rating, with mean scores of 0.37 and 0.13, respectively (p = 0.012).

CONCLUSION: The findings suggest that the respondents' perspectives may influence MBI-C scores. Significant differences may exist between self-rating and informant rating in decreased motivation, affective dysregulation, and social inappropriateness domains. Clinicians should exercise caution when interpreting the results from different information sources.},
}

Humans
Male
Female
*Cognitive Dysfunction/diagnosis/psychology
Aged
Neuropsychological Tests
Middle Aged
Aged, 80 and over
Psychiatric Status Rating Scales
Checklist
Mental Status and Dementia Tests

@article {pmid41448751,
year = {2025},
author = {Liu, S and Wang, L and Li, S and Xu, G},
title = {[Effects of 40 Hz light flicker stimulation on hippocampal-prefrontal neural activity characteristics during working memory tasks in Alzheimer's disease model rats].},
journal = {Sheng wu yi xue gong cheng xue za zhi = Journal of biomedical engineering = Shengwu yixue gongchengxue zazhi},
volume = {42},
number = {6},
pages = {1107-1114},
doi = {10.7507/1001-5515.202503009},
pmid = {41448751},
issn = {1001-5515},
mesh = {Animals ; *Alzheimer Disease/physiopathology/therapy ; *Memory, Short-Term/physiology/radiation effects ; *Prefrontal Cortex/physiopathology ; *Hippocampus/physiopathology/physiology ; Rats, Wistar ; Rats ; Disease Models, Animal ; Male ; *Photic Stimulation ; Maze Learning ; },
abstract = {40 Hz light flicker stimulation is deemed to hold considerable promise in the treatment of Alzheimer's disease (AD). However, whether its long-term effect can improve working memory and its related mechanisms remains to be further explored. In this study, 21 adult Wistar rats were randomly divided into the AD light-stimulation group, the AD group and the control group. AD models were established in the first two of these groups, with the light-stimulation group receiving long-term 40 Hz light flicker stimulation. Working memory performance across groups was subsequently evaluated using the T-maze task. To investigate the potential neural mechanisms underlying the effects of 40 Hz light stimulation on working memory, we examined changes in neuronal excitability within the hippocampus (HPC) and medial prefrontal cortex (mPFC), as well as alterations in inter-regional synchronization of neural activity. The findings demonstrated that prolonged 40 Hz light stimulation significantly improved working memory performance in AD model rats. Furthermore, the intervention enhanced the synchronization of neural activity between the hippocampus (HPC) and medial prefrontal cortex (mPFC), as well as the efficiency of information transfer, primarily mediated by theta and low-frequency gamma oscillations. This study provides theoretical support for exploring the mechanisms of 40 Hz light flicker stimulation and its further clinical application in the prevention and treatment of Alzheimer's disease.},
}

Animals
*Alzheimer Disease/physiopathology/therapy
*Memory, Short-Term/physiology/radiation effects
*Prefrontal Cortex/physiopathology
*Hippocampus/physiopathology/physiology
Rats, Wistar
Rats
Disease Models, Animal
Male
*Photic Stimulation
Maze Learning

@article {pmid41448719,
year = {2025},
author = {Cowan, D and Siemon, J and Sarkar, A and Plagos, R and Speelziek, E and Harder, K and Gregg, S},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e102891},
doi = {10.1002/alz70858_102891},
pmid = {41448719},
issn = {1552-5279},
mesh = {Humans ; *Dementia/diagnosis/psychology/therapy ; *Mental Status and Dementia Tests ; *Neuropsychological Tests ; *Health Personnel/education ; Male ; Female ; Education ; Aged ; },
abstract = {BACKGROUND: Cognitive assessment is a necessary part of diagnosing Alzheimer's Disease and related disorders, monitoring disease progression, and measuring treatment effectiveness. Geriatricians and other healthcare providers have observed that cognitive tests are often not administered in a standardized manner, compromising their validity. As well, they are often not administered on the appropriate population or in the appropriate setting. The Cognitive Assessment Tools (CAT) workshop is a half-day, interactive, small group program delivered virtually by trained and experienced healthcare providers. The CAT workshop equips participants with knowledge on the appropriate usage, interpretation, and standardized administration and scoring of cognitive assessment tools, including the Standardized Mini-Mental Status Exam (sMMSE), Montreal Cognitive Assessment (MoCA®), Trail Making Test (TMT), Clock Drawing Test (CDT), and Geriatric Depression Scale (GDS). This workshop was previously offered in person, in both small- and large-group formats. The present study aims to evaluate outcomes of this novel workshop delivered in a virtual format.

METHOD: Workshop participants completed pre- post-workshop surveys. Participants utilized a scale from 1 (no proficiency) to 7 (mastery) to report their self-perceived competency.

RESULT: 53 participants from 9 workshops completed pre- and post- workshop evaluations (57% response rate). Participants' professions included: nursing (56%), social work (9%), occupational therapy (6%), therapeutic recreation (6%), medicine (4%), physiotherapy (4%), personal support worker (4%), and other (11%). Results of paired t-tests indicated a significant difference between before and after scores for all cognitive assessments. Pre-post mean differences for each cognitive test: sMMSE=1.81; MoCA®=1.70; TMT=2.47; CDT=1.75; GDS=2.11, all p <0.001. There was a significant difference in participants' understanding of why cognitive assessments are used (pre-post mean difference = 1.15), and their knowledge of selecting the appropriate tool to use (pre-post mean difference = 2.21), both p <0.001. Ninety-four percent of participants would recommend the workshop to a colleague.

CONCLUSION: The CAT workshop is associated with significant increases in healthcare workers' self-reported competency in selecting, administering, scoring and interpreting common cognitive assessment tools. The workshop attracts a variety of healthcare and social care professionals, and is well-received by learners.},
}

Humans
*Dementia/diagnosis/psychology/therapy
*Mental Status and Dementia Tests
*Neuropsychological Tests
*Health Personnel/education
Male
Female
Education
Aged

@article {pmid41448667,
year = {2025},
author = {Cole, GM and Zhu, C and Manglani, K and Hou, K and Bombino, A and Jones, M and Eisenberg, DS and Frautschy, SA},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106249},
doi = {10.1002/alz70859_106249},
pmid = {41448667},
issn = {1552-5279},
mesh = {Animals ; Mice, Transgenic ; Mice ; *alpha-Synuclein/metabolism/genetics ; *Drug Development ; Disease Models, Animal ; Brain/drug effects/metabolism/pathology ; Humans ; Parkinson Disease/drug therapy/genetics ; tau Proteins/metabolism ; },
abstract = {BACKGROUND: Pre-Fibrillar oligomeric and insoluble fibrillar aggregates of alpha-synuclein (aSyn) accumulate and contribute to the neurodegenerative decline in Parkinson Disease (PD) and other synucleinopathies and frequently occur as co-morbidities in the major tauopathy, Alzheimer Disease (AD). Familial autosomal dominant PD aSyn A53T mutations which promote aggregation cause age-related aSyn and tau pre-fibrillar oligomers and insoluble aSyn fibrillar deposits, neurodegeneration and motor deficits in hemizygous A53T aSyn transgenic mice.

METHOD: To test a candidate fibril structure-based therapeutic candidate we treated aSyn deposit-bearing 24 month old heterozygous A53T M83 mice for 6 weeks with a formulation of CNS11g, a small molecule designed to specifically fit an aSyn fibril site required for aggregation and previously demonstrated to disaggregate both pre-existing aSyn and tau fibrils in cell free systems.

RESULT: Oral gavage produced brain levels above the in vitro ED50 for disaggregation and ameliorated motor deficits with no evidence of toxicity compared with the vehicle group. CNS11g reduced levels of putatively neurotoxic, SDS-stable, high molecular weight soluble aSyn aggregates detected above 256kD by Western blot analysis in spinal cord and brainstem as well as tau oligomers in spinal cord. Quantitative ICC for p129S aSyn deposits and reactive glia, supported a significant treatment effect, but there was no effect on detergent insoluble p129S aSyn. Our late intervention results provide evidence for effective oral CNS11g delivery, safety and efficacy in reducing motor deficits and soluble p129S aSyn and tau oligomers and aSyn deposits by ICC without biochemical evidence for reducing pre-existing insoluble fibrillar aSyn deposits with this treatment paradigm.

CONCLUSION: While higher or longer dosing might disaggregate and clear insoluble fibrils, this initial study suggests oral dosing produces pleiotropic CNS activity against both aSyn and tau pre-fibrillar oligomers implicated in the neurotoxicity, seeding and spreading of two major proteinopathies.},
}

Animals
Mice, Transgenic
Mice
*alpha-Synuclein/metabolism/genetics
*Drug Development
Disease Models, Animal
Brain/drug effects/metabolism/pathology
Humans
Parkinson Disease/drug therapy/genetics
tau Proteins/metabolism

@article {pmid41448660,
year = {2025},
author = {Cohen, S and Andreozzi, E and Hersch, S and Gee, M and Irizarry, MC and Kramer, LD},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e104695},
doi = {10.1002/alz70859_104695},
pmid = {41448660},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Drug Development ; *Antibodies, Monoclonal, Humanized/administration & dosage/therapeutic use ; Injections, Subcutaneous ; Cognitive Dysfunction/drug therapy ; },
abstract = {BACKGROUND: Lecanemab is a novel, humanized monoclonal antibody, which has demonstrated the ability to substantially reduce markers of amyloid and slow clinical decline on multiple measures of cognition and function in early Alzheimer's disease (AD). A subcutaneous administration of lecanemab is in development, to improve patient and caregiver convenience relative to the intravenous route of administration as well as eliminate the time and resources needed for preparation and administration of intravenous infusions. Herein, we highlight the potential benefits and place in therapy for a subcutaneous formulation of lecanemab based on currently available data and relevant literature.

METHODS: Utilizing the currently available data, expert consensus treatment guidelines, and available AD literature, we will place the results of the subcutaneous lecanemab clinical program in context of the current treatment paradigm in early AD. Results of recent human factors validation study which evaluated whether the new lecanemab autoinjector can be safely and effectively used under the expected use environments will also be presented. The human factors study assessed task performance of 110 trained and untrained participants (patients with self- or caregiver-reported diagnosis of mild cognitive impairment or mild AD [n=63], caregivers [n=32], and healthcare providers [HCPs; n=15]) using the lecanemab autoinjector under the expected use environments/conditions without patterns of use error which could cause serious harm to a user, where harm is defined to include compromised medical care (e.g., incomplete dosing).

RESULTS: The continuous nature of AD pathophysiological process requires ongoing therapy. Given the burden of frequent intravenous injections, a subcutaneous lecanemab formulation would be a welcome addition for providing on-going maintenance therapy. The newly developed lecanemab autoinjector offers an additional administration option with a weekly dosing schedule while enabling easier administration, increased access to the medication, and reduced burden. The human factors study revealed that a majority of HCPs (80%; 12/15), caregivers (84.4%; 27/32), and patients (82.5%; 52/63) were observed to administer a full dose successfully.

CONCLUSIONS: Weekly subcutaneous lecanemab has the potential for a prominent place in therapy by providing comparable efficacy relative to intravenous formulation with a more convenient and accessible administration by patients, caregivers or HCPs.},
}

Humans
*Alzheimer Disease/drug therapy
*Drug Development
*Antibodies, Monoclonal, Humanized/administration & dosage/therapeutic use
Injections, Subcutaneous
Cognitive Dysfunction/drug therapy

@article {pmid41448659,
year = {2025},
author = {Rezai, AR and Teixeira, CVL and Ranjan, M and Adams, G and Arsiwala, T and Finomore, V and Haut, MW},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e100580},
doi = {10.1002/alz70858_100580},
pmid = {41448659},
issn = {1552-5279},
mesh = {Humans ; *Cognitive Dysfunction/therapy/diagnostic imaging/psychology ; Pilot Projects ; Male ; Female ; Aged ; Positron-Emission Tomography ; *Alzheimer Disease/therapy/psychology/diagnostic imaging ; Magnetic Resonance Imaging ; Neuropsychological Tests ; Brain/diagnostic imaging ; *Ultrasonic Therapy/methods ; Aged, 80 and over ; Treatment Outcome ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) presents a major public health challenge with few effective therapeutic options. Monoclonal antibodies targeting β-amyloid show promise, but their clinical efficacy remains modest. As such, combining pharmacological and non-pharmacological interventions to slow cognitive decline has become a key area of research. Low-intensity focused ultrasound (LIFU), a non-invasive neuromodulation technique with excellent spatio-temporal precision, has emerged as a potential therapeutic option for AD. Our group has had success in using LIFU for BBBOpening This pilot study aims to assess the safety, feasibility, and tolerability of LIFU as an adjunct treatment for individuals with mild cognitive impairment (MCI) due to AD (NCT05997030).

METHODS: This open-label pilot study includes participants with amyloid positive MCI who undergo a single session of LIFU targeting the nucleus accumbens, hippocampus, and entorhinal cortex. Safety is assessed using cognitive evaluations, brain MRI, and FDG PET scans at baseline and follow-up intervals to monitor any adverse events and metabolic and cognitive changes.

RESULTS: Three amyloid positive patients with MCI (two males and one female) underwent a single LIFU neuromodulation session. The FUS procedure was safe and well-tolerated. There were no new neurological or imaging abnormalities. Cognitive assessments showed no changes in memory and attention, but there were slight increases in scores at the short-term follow-up period of 07 and 30 days after the FUS procedure. The results will be updated as the clinical trial progresses and presented at the meeting.

CONCLUSIONS: These preliminary findings suggest that LIFU neuromodulation is safe and may offer cognitive benefits for individuals with amyloid-positive MCI. This study highlights the promise of FUS technology as a novel adjuvant therapeutic approach in AD.},
}

Humans
*Cognitive Dysfunction/therapy/diagnostic imaging/psychology
Pilot Projects
Male
Female
Aged
Positron-Emission Tomography
*Alzheimer Disease/therapy/psychology/diagnostic imaging
Magnetic Resonance Imaging
Neuropsychological Tests
Brain/diagnostic imaging
*Ultrasonic Therapy/methods
Aged, 80 and over
Treatment Outcome

@article {pmid41448651,
year = {2025},
author = {Pascual-Lucas, M and Lacosta, AM and Montañés, M and Canudas, J and Loscos, J and Piñol-Ripoll, G and Terencio, J and Boada, M},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102589},
doi = {10.1002/alz70859_102589},
pmid = {41448651},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Male ; Female ; Double-Blind Method ; *Amyloid beta-Peptides/immunology ; Aged ; *Cognitive Dysfunction/drug therapy ; *Drug Development ; *Peptide Fragments/immunology ; *Alzheimer Vaccines/therapeutic use ; Treatment Outcome ; Middle Aged ; },
abstract = {BACKGROUND: ABvac40 is an investigational vaccine targeting Aβ40 for the treatment of Alzheimer's disease (AD). Aβ40 plays a significant role in several pathological processes of AD, especially concerning amyloid deposition in blood vessels. Phase 2 trial results (NCT03461276) demonstrated a favorable safety profile, robust immunogenicity, and promising trends in cognitive outcomes and brain atrophy. To further explore the therapeutic potential of ABvac40, we aimed to assess clinical relevance at individual patient level by evaluating meaningful within-patient changes (MWPC). This approach examines the proportion of patients experiencing significant deterioration across treatment groups, providing a method to assess the meaningfulness of treatment effects in progressive conditions like AD.

METHOD: AB1601 was a randomized, double-blind, placebo-controlled phase 2 study in patients with mild cognitive impairment or very mild AD. MWPC was defined as a decline of ≥3 points in MMSE at two consecutive visits over 24 months. Cox proportional hazard models assessed the risk of MWPC, adjusting for MMSE baseline score, baseline age, APOE Ɛ4 carrier status, clinical stage and baseline use of AD medication. Patients treated with ABvac40 were stratified by CSF antibody levels into two groups: high levels (Q4) and low levels (Q1-Q3). Analyses were conducted in the PPc analysis set.

RESULT: A total of 97 patients were included in the PPc analysis set. Of these, 69 (71.1%) were amyloid-PET positive. In the overall population, ABvac40 significantly reduced the risk of MWPC over 24 months compared to placebo (HR=0.47; 95% CI 0.27-0.85; P=0.012). In the amyloid-PET positive subgroup, ABvac40 showed a more pronounced protective effect (HR=0.38; 95% CI 0.20-0.75; P=0.005). Within this subgroup, patients with lower antibody levels had a 63% lower risk of MWPC (HR=0.37; 95% CI 0.16-0.83; P=0.016), while those with higher antibody levels showed an 81% reduction (HR=0.19; 95% CI 0.04-0.84; P=0.029).

CONCLUSION: ABvac40 treatment significantly reduced clinically meaningful cognitive decline, particularly in amyloid-PET positive patients, with the strongest effects in those with the highest antibody levels. These findings highlight ABvac40's potential to influence disease progression in early-stage AD and warrant further studies to explore its impact on brain vessels as potential driver of the observed cognitive benefits.},
}

Humans
*Alzheimer Disease/drug therapy
Male
Female
Double-Blind Method
*Amyloid beta-Peptides/immunology
Aged
*Cognitive Dysfunction/drug therapy
*Drug Development
*Peptide Fragments/immunology
*Alzheimer Vaccines/therapeutic use
Treatment Outcome
Middle Aged

@article {pmid41448637,
year = {2025},
author = {Li, R and Wood, J},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e101426},
doi = {10.1002/alz70859_101426},
pmid = {41448637},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Drug Development ; *Information Dissemination/methods ; *Databases, Factual ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) research increasingly relies on the ability to access and analyze diverse datasets to advance scientific understanding and therapeutic development. Vivli, a leading global data-sharing platform, facilitates data discovery and interoperability by providing researchers with access to a vast repository of clinical trial data across multiple therapeutic areas. Currently, Vivli hosts 88 individual participant level datasets related to Alzheimer's disease, offering an unprecedented opportunity to drive innovation through secondary data analyses. Leveraging its experience in conducting data challenges across various fields, Vivli is prepared to collaborate with the Alzheimer's Disease Data Initiative to launch a new challenge aimed at accelerating discoveries in AD research.

METHOD: Vivli employs a comprehensive data-sharing ecosystem that promotes interoperability through FAIR principles. Through partnerships with industry, academia, and non-profit organizations, Vivli makes high-quality datasets available and enables researcher access to raw data via a secure and user-friendly platform. The proposed AD data challenge, in collaboration with the AD Data Initiative, will focus on leveraging Vivli's interoperable datasets to address critical research questions and engage a global research community.

RESULT: To date, Vivli has successfully conducted numerous data challenges that have resulted in actionable insights and novel findings across various therapeutic areas. These challenges have fostered cross-disciplinary collaboration and innovation, demonstrating the value of secondary data analyses. In Alzheimer's disease, Vivli's datasets provide a rich resource for exploring disease progression, treatment efficacy, and biomarker discovery. The upcoming challenge with the AD Data Initiative aims to attract multidisciplinary teams, encouraging the application of advanced analytical techniques such as AI and machine learning to uncover new insights in AD.

CONCLUSION: Vivli's platform is uniquely positioned to enhance Alzheimer's disease research by enabling data access and fostering a collaborative research environment. The planned data challenge with the AD Data Initiative represents a unique opportunity to harness the collective expertise of the global research community and accelerate progress in AD. By enhancing dataset discovery interoperability and promoting FAIR data-sharing principles, Vivli continues to drive meaningful advancements in the field, ultimately contributing to improved patient outcomes and therapeutic innovation.},
}

Humans
*Alzheimer Disease/drug therapy
*Drug Development
*Information Dissemination/methods
*Databases, Factual

@article {pmid41448631,
year = {2025},
author = {Praween, S and Vishwas, S},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e100764},
doi = {10.1002/alz70859_100764},
pmid = {41448631},
issn = {1552-5279},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Depsides/therapeutic use/pharmacology ; Rosmarinic Acid ; Animals ; *Drug Development ; *Neuroprotective Agents/therapeutic use/pharmacology ; *Cinnamates/therapeutic use/pharmacology ; *Antioxidants/therapeutic use/pharmacology ; Oxidative Stress/drug effects ; Anti-Inflammatory Agents/therapeutic use ; Disease Models, Animal ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline, memory loss, and behavioral changes due to degeneration of cholinergic neurons in the cerebral cortex and hippocampus part of the brain. The underlying mechanisms involve oxidative stress, neuroinflammation, and the accumulation of amyloid-beta plaques. As current treatments offer limited efficacy, exploring alternative therapeutic agents has become a key area of research. Rosmarinic acid (RA), a polyphenolic compound found in various herbs, has gained attention for its antioxidant, anti-inflammatory, anti-amyloid, and anti-apoptosis properties, which may offer potential benefits in the treatment of AD.

METHOD: This review compiles findings from preclinical and clinical studies investigating the effects of RA for the treatment of AD. Studies were identified through database searches and included both in vitro (cellular) and in vivo (animal) models of AD, as well as clinical trials examining RA's impact on cognitive function, neuroinflammation, and oxidative stress.

RESULT: Experimental evidence suggests that RA exhibits anti-inflammatory, antioxidant, and neuroprotective effects that could help mitigate the hallmarks of AD. In animal models, RA has been shown to reduce amyloid-beta plaque deposition, decrease oxidative stress, and improve cognitive performance. Clinical studies, although limited, have reported positive trends in cognitive improvement and symptom management following RA supplementation, suggesting its potential as a supportive treatment.

CONCLUSION: RA demonstrates significant promise as a therapeutic agent for AD. Its multifaceted mechanisms of action, including anti-inflammatory, antioxidant, and neuroprotective properties, support its potential role in mitigating the pathological features of AD. Further clinical trials are needed to establish its efficacy and optimal use in AD management, but RA could offer a novel adjunct to existing treatments in combating this devastating disorder.},
}

*Alzheimer Disease/drug therapy
Humans
*Depsides/therapeutic use/pharmacology
Rosmarinic Acid
Animals
*Drug Development
*Neuroprotective Agents/therapeutic use/pharmacology
*Cinnamates/therapeutic use/pharmacology
*Antioxidants/therapeutic use/pharmacology
Oxidative Stress/drug effects
Anti-Inflammatory Agents/therapeutic use
Disease Models, Animal

@article {pmid41448615,
year = {2025},
author = {Kern, R and Lee, L and Zusterzeel, R and Konisky, A and Hempel, E and Leach, JM and Seshagiri, CV and Hajos, M and Howell, C},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e100579},
doi = {10.1002/alz70859_100579},
pmid = {41448615},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/therapy ; *Drug Development ; Randomized Controlled Trials as Topic ; },
abstract = {BACKGROUND: Cognito Therapeutics is advancing a convenient, at-home neuromodulation treatment option that leverages non-invasive audiovisual stimulation to modify the biology and clinical course of Alzheimer's disease. The OVERTURE (NCT03556280) randomized (RCT) and open label extension (OLE) clinical trials evaluated our non-invasive device (Spectris[TM]) in participants with mild-moderate Alzheimer's disease (AD). The almost fully enrolled HOPE pivotal trial (NCT05637801) is being conducted across 60 US clinical trial sites in mild-moderate Alzheimer's disease. We will discuss the impact Spectris[TM] may have on patients, their families, and the broader health system to address the important unmet need in Alzheimer's disease.

METHOD: The OVERTURE RCT compared one-hour, daily, at-home, active vs. sham treatment for six months (2:1 randomization). The OVERTURE OLE continued open-label treatment in RCT completers for an additional 12 months. The ongoing HOPE study is evaluating Spectris[TM] in a 12-month RCT and 12-month OLE (NCT06245031) in participants with mild-moderate AD.

RESULT: OVERTURE RCT and OLE clinical and MRI biomarker results will be reviewed and discussed. We will compare the OVERTURE and HOPE study designs and baseline characteristics as well as key insights gained from the evaluation of a daily, at-home, non-invasive neuromodulation therapy in mild-moderate Alzheimer's participants.

CONCLUSION: Spectris[TM] potentially offers a safe, effective and cost-effective treatment option and may expand the range of treatment options available for patients with Alzheimer's disease.},
}

Humans
*Alzheimer Disease/therapy
*Drug Development
Randomized Controlled Trials as Topic

@article {pmid41448609,
year = {2025},
author = {Keil, SA and Zhou, L and Wang, XH and Nguyen, TD and Chiang, G and Li, Y and Butler, TA},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104292},
doi = {10.1002/alz70856_104292},
pmid = {41448609},
issn = {1552-5279},
mesh = {Humans ; *Sleep Apnea, Obstructive/therapy/diagnostic imaging/cerebrospinal fluid ; *Glymphatic System/diagnostic imaging ; Magnetic Resonance Imaging ; Male ; *Biomarkers/cerebrospinal fluid ; Female ; Continuous Positive Airway Pressure ; Middle Aged ; *Brain/diagnostic imaging/pathology ; Aged ; *Cerebrospinal Fluid ; },
abstract = {BACKGROUND: Obstructive sleep apnea (OSA) affects an estimated 936 million adults globally. When left untreated, OSA increases risk of comorbid cardiovascular, metabolic, and neurodegenerative diseases including Alzheimer's. Continuous positive airway pressure (CPAP) remains the gold standard of treatment, ameliorating sleep apnea, reducing comorbidities, and improving brain health. However, difficulties with CPAP use results in 30-80% non-compliance. Identifying CPAP's therapeutic mechanisms may help develop alternative interventions for the millions who cannot benefit from CPAP. Recent studies suggest OSA impacts brain fluid clearance, including the glymphatic system. The glymphatic system is a brain-wide network of perivascular spaces (PVS) which facilitate clearance of metabolic waste during sleep. Clinical evaluation of glymphatic system PVS has proved challenging. MRI-based enhanced PVS contrast (EPC) which defines enlarged white matter PVS, and novel whole brain parenchymal cerebrospinal fluid (pCSF) mapping which delineates CSF water fractions in PVS including pCSF offer potential solutions. Here, we evaluate EPC and pCSF derived glymphatic fluid burden in CPAP-treated and untreated OSA subjects and healthy age-matched controls (HC).

METHODS: Cross-sectional analysis (n = 32) involved HC, CPAP-treated OSA, and untreated OSA groups. Neuroimaging included 3T MRI acquired T1W, multi-echo FAST-T2 for pCSF, and T2W sequences. Image processing was performed with FreeSurfer for ROI parcellation and an in-house MATLAB code for pCSF mapping.

RESULTS: Across multiple regions, untreated participants exhibit the highest pCSF burden, while CPAP treatment appears to align closely with HC (Figure 1A-B). In the temporal lobe, untreated OSA participants exhibited 6.01% pCSF which is significantly higher (p <0.05) than CPAP-treated (5.26%) and HC (5.32%). Comparatively, there was no significant difference in EPC across all groups (Figure 1C 1.4-1.7%). No difference in cortical volumes was observed across groups, suggesting glymphatic fluid findings using pCSF are not related to atrophy.

CONCLUSION: These findings underscore the impact of OSA on the brain's glymphatic system, highlighting glymphatic dysfunction as a potential contributor to the downstream effect of untreated OSA. Comparative findings of EPC and pCSF suggest that pCSF may be a more sensitive approach to evaluating sublet changes in glymphatic fluid burden. Further research is necessary to substantiate these findings in a longitudinal within-subject cohort before and after CPAP treatment.},
}

Humans
*Sleep Apnea, Obstructive/therapy/diagnostic imaging/cerebrospinal fluid
*Glymphatic System/diagnostic imaging
Magnetic Resonance Imaging
Male
*Biomarkers/cerebrospinal fluid
Female
Continuous Positive Airway Pressure
Middle Aged
*Brain/diagnostic imaging/pathology
Aged
*Cerebrospinal Fluid

@article {pmid41448564,
year = {2025},
author = {Feldman, OJ and Ruthirakuhan, M and Herrmann, N and Gallagher, D and Marotta, G and Kiss, A and Wang, HJJ and Kang, Y and Black, SE and Lanctôt, KL},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e103582},
doi = {10.1002/alz70857_103582},
pmid = {41448564},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; *Alzheimer Disease/complications/drug therapy/psychology ; Aged, 80 and over ; *Psychomotor Agitation/drug therapy/etiology ; Cross-Over Studies ; Psychiatric Status Rating Scales ; },
abstract = {BACKGROUND: Agitation is one of the most prevalent neuropsychiatric symptoms (NPS) of Alzheimer's disease (AD). A crossover trial of nabilone for agitation in AD found that nabilone was effective in treating agitation. We aimed to identify which clinical characteristics predicted response to nabilone intervention for agitation.

METHOD: Twenty-two potential clinical characteristics were identified a priori. Characteristics were analyzed for their ability to predict improvements on the Cohen-Mansfield Agitation Inventory (CMAI). Each characteristic was categorically split and compared with univariate analyses: characteristics showing differences ≥8 CMAI points were included in a multivariate regression to model interactions between the treatment and characteristics. Index scores were calculated to represent the likelihood of response to treatment and results were grouped into quartiles. Multicollinearity of the characteristics was assessed.

RESULT: 35 patients (28 males (80%), mean age [SD] 87.0 [10.2] years, CMAI 67.4 [17.7], standardized Mini-Mental State Exam (sMMSE) 6.6 [6.8]) had complete data for clinical predictors, allowing for 70 cases to be analyzed. Six predictors met criteria for inclusion in multivariate modelling, where nabilone was more effective in participants with sMMSE scores ≥6 (Δ level estimates = -12.0), higher levels of pain (-17.1), apathy (-8.7), appetite and eating changes (-9.7), and not taking cholinesterase inhibitors (ChEIs) (-8.4).

CONCLUSION: AD patients with pain, apathy and appetite changes, and with less cognitive impairment and not on ChEIs, were most likely to benefit from nabilone. If replicated with phase 3 data, these predictors may assist in guiding clinicians on who is likely to benefit from nabilone when managing agitation.},
}

Humans
Male
Female
Aged
*Alzheimer Disease/complications/drug therapy/psychology
Aged, 80 and over
*Psychomotor Agitation/drug therapy/etiology
Cross-Over Studies
Psychiatric Status Rating Scales

@article {pmid41448509,
year = {2025},
author = {Kim, N and Jeon, JY and Seo, J and Lee, Y and Kim, HJ and Kim, JS},
title = {A Combined Model of Convolutional Neural Networks and Graph Attention Networks for Improved Classification of Mild Cognitive Impairment.},
journal = {NeuroImage},
volume = {},
number = {},
pages = {121674},
doi = {10.1016/j.neuroimage.2025.121674},
pmid = {41448509},
issn = {1095-9572},
abstract = {Mild cognitive impairment (MCI), a precursor of Alzheimer's disease (AD), underscores the importance of early diagnosis and treatment. With an aging global population, AD prevalence is rising, necessitating more precise diagnostic methods. Deep learning technology shows promise for MCI and AD classification, but existing convolutional neural network (CNN) and graph attention network (GAT) models have limitations in capturing brain structural features and detecting microlesions. To address these issues, we propose a novel approach combining a CNN and modified GAT model to improve MCI classification. Magnetic resonance imaging volume data were analyzed using a CNN, whereas cortical thickness data were modeled using a GAT, leveraging their complementary strengths. Preprocessing involved extracting brain's structural features via the CIVET pipeline, and t-SNE was used to visualize the data's high-dimensional distribution. Final classification was performed using a multilayer perceptron, integrating feature vectors from both models. Performance evaluation metrics included the area under the curve (AUC), F1-score, sensitivity, and specificity. The combined CNN-GAT model outperformed existing single-model approaches, particularly in MCI classification, effectively distinguishing subtle variations between normal aging and MCI. The combined CNN-GAT model improved MCI classification performance by addressing the limitations of existing approaches. By capturing brain structural features and inter-regional relationships, it offers significant potential for advancing early diagnosis and treatment strategies for neurodegenerative diseases. Future efforts will focus on enhancing performance through additional data optimization.},
}

@article {pmid41448242,
year = {2025},
author = {Cohen, S and Cotton, S and Fortea, J and Kowa, H and Kr, N and Tarazona, LRS and Walker, C},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e100805},
doi = {10.1002/alz70858_100805},
pmid = {41448242},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; Cross-Sectional Studies ; *Cognitive Dysfunction/diagnosis/psychology/therapy ; *Alzheimer Disease/diagnosis/psychology/therapy ; Mental Status and Dementia Tests/statistics & numerical data ; *Dementia/diagnosis/psychology ; Aged, 80 and over ; Early Diagnosis ; },
abstract = {BACKGROUND: With the emergence of disease modifying treatments, the importance of early diagnosis of mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease (AD) has increased. This research explores the global clinical care pathway with the aim of highlighting areas for improvement for early and accurate diagnosis.

METHOD: Data were drawn from the Adelphi Real World AD Disease Specific Programme™, a cross-sectional survey of physicians and their patients in Canada, France, Germany, Italy, Spain, the United Kingdom, Japan, and the United States between December 2022 - March 2024. Physicians reported data on patient's diagnostic pathway, Mini-Mental State Examination (MMSE) score at first consultation, and treatment for approximately their next nine consulting patients diagnosed with MCI due to AD or dementia due to AD (clinically diagnosed or biomarker confirmed). Patients self-reported their reasons for delaying consultation. Data was grouped by MMSE. Analyses were descriptive.

RESULT: Overall, 829 physicians reported data for 5654 patients; 726 self-completed forms. Patient mean (standard deviation) age was 76.7 (8.4) years and 48.0% were male. Of those with an MMSE score at first consultation, 20.6% had 26-30, 47.2% 21-25, 29.9% 11-20, and 2.3% 0-10. Time from symptom onset to first consultation was a median [interquartile range] of 20.7 [4.6, 52.0] weeks. Patients reported delaying first visiting a physician (75.1%), mainly due to believing their memory problems were a part of normal ageing (72.3%). Most patients first consulted a primary care physician (73.4% of patients with an MMSE of 26-30; 58.7% 0-10), of which 72.4% and 45.5%, respectively, were referred on for diagnosis. Key diagnostic tools were behavioural/cognitive assessments (91.8%), feedback from patient/patient's family (89.3%), and non-AD specific blood tests (88.7%). Biomarker testing was infrequent (11.8%). When treatment was prescribed, lack of efficacy was the key driver for change in initial treatment (48.9%).

CONCLUSION: Our results highlight a lack of awareness of early symptoms, inconsistent referral, and infrequent utilization of AD specific biomarkers. Addressing these challenges is pivotal to facilitate early, accurate diagnosis and intervention. Lack of efficacy was the main reason for changing initial treatment, indicating the need for better treatment options.},
}

Humans
Male
Female
Aged
Cross-Sectional Studies
*Cognitive Dysfunction/diagnosis/psychology/therapy
*Alzheimer Disease/diagnosis/psychology/therapy
Mental Status and Dementia Tests/statistics & numerical data
*Dementia/diagnosis/psychology
Aged, 80 and over
Early Diagnosis

@article {pmid41448230,
year = {2025},
author = {Padder, S and Campagna, JJ and Chandra, S and Teter, B and Cohn, W and Pham, J and Song, Y and Jagodzinska, B and Vadivel, K and Alam, MP and Bilousova, T and Young, M and Elias, CJ and Marcucci, J and Flacau, I and Jackman, A and Wi, D and Zhu, C and Spilman, P and Jung, M and Bredesen, DE and John, V},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e101293},
doi = {10.1002/alz70859_101293},
pmid = {41448230},
issn = {1552-5279},
mesh = {Animals ; *Sirtuin 1/metabolism/genetics ; Mice, Transgenic ; *Alzheimer Disease/drug therapy/metabolism/genetics ; Disease Models, Animal ; *Apolipoprotein E4/genetics/metabolism ; Mice ; Humans ; Hippocampus/metabolism/drug effects ; Neurons/drug effects/metabolism ; Maze Learning/drug effects ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by amyloid plaques and tau tangles, with apolipoprotein E4 (ApoE4) recognized as a strong genetic risk factor for sporadic AD. ApoE4 has been shown to repress the expression of Sirtuin 1 (SirT1), a key neuroprotective protein, contributing to disease progression. This study describes the discovery and preclinical evaluation of DDL-218, a small-molecule SirT1 enhancer targeting ApoE4 to mitigate its repressive effects on SirT1.

METHOD: A high-throughput screening in N2a-apoE4 cell line identified SirT1 enhancer candidate compounds. Lead compounds were identified through medicinal chemistry and in silico modeling. In vitro testing in ApoE4-expressing neuronal cells and in vivo acute and chronic studies using ApoE4(TR):5xFAD transgenic AD mouse models were conducted. Protein interactions were examined through affinity purification, proteomics, and chromatin immunoprecipitation. Gene expression changes in SirT1, NYFB and PRMT5 were measured by qRT-PCR. Memory improvement was assessed using Barnes Maze test. Hippocampal tissue from DDL-218- and vehicle-treated mice underwent global proteomics and thermal proteome profiling (TPP) to identify differentially expressed proteins and elucidate the mechanism of action of DDL-218.

RESULT: DDL-218 significantly increased SirT1 protein and mRNA levels in neuronal cells by upregulating transcription factor NFYB and enzyme PRMT5. Drug treatment led to displacement of ApoE4 from the SirT1 promoter, allowing enhanced SirT1 expression. In AD model mice, DDL-218 treatment improved memory performance observed in the Barnes Maze test, and enhanced SirT1, NFYB, and PRMT5 mRNA in the brain. Proteomics revealed that DDL-218 upregulated proteins associated with neuronal function, including PTprn2, which plays a role in synaptic plasticity. Additionally, DDL-218 showed favorable brain penetration and no observable adverse effects.

CONCLUSION: DDL-218 successfully enhanced SirT1 expression by counteracting ApoE4's repressive effects, demonstrating potential as a therapeutic strategy for AD. DDL-218 improved memory and key neural pathways, showing promise in preclinical models. The observed cognitive improvements in the mouse model support further investigation of DDL-218 as a novel treatment for Alzheimer's, targeting ApoE4-driven disease mechanisms. Future studies will establish protein targets of DDL-218 and clarify its mechanism in increasing NFYB mRNA levels. Additionally, we will evaluate its safety profile and efficacy in other ApoE4-expressing in vivo models.},
}

Animals
*Sirtuin 1/metabolism/genetics
Mice, Transgenic
*Alzheimer Disease/drug therapy/metabolism/genetics
Disease Models, Animal
*Apolipoprotein E4/genetics/metabolism
Mice
Humans
Hippocampus/metabolism/drug effects
Neurons/drug effects/metabolism
Maze Learning/drug effects

@article {pmid41448226,
year = {2025},
author = {Atkins, KJ and Brailow, TR and Weigand, AJ and Tsoy, E and Racke, MK and Larsen, J and Reck-Rivera, C and Erlhoff, SJ and Lago, AL and Windon, CC and Dilworth-Anderson, P and Possin, KL},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e103571},
doi = {10.1002/alz70857_103571},
pmid = {41448226},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *Alzheimer Disease/diagnosis/blood ; Aged ; Biomarkers/blood ; Reproducibility of Results ; Neuropsychological Tests ; Amyloid beta-Peptides/blood ; Aged, 80 and over ; Middle Aged ; Feasibility Studies ; *Cognitive Dysfunction/diagnosis ; },
abstract = {BACKGROUND: Delays in the diagnosis of Alzheimer's disease and related dementias (ADRD) impede access to disease-modifying interventions, supportive care, and the opportunity to participate in research. We examined the feasibility, acceptability, reliability, and validity of a novel home-based diagnostic pathway that leverages advances in digital cognitive assessments and plasma biomarkers.

METHOD: Ethnically diverse participants from the UCSF Alzheimer's Disease Research Center (ADRC) were recruited and completed in-home digital cognitive assessment (TabCAT Brain Health Assessment) and blood biospecimen collection with a Quest mobile phlebotomist, as well as parallel procedures in the ADRC. Participants completed testing in their preferred language (22 English, 19 Spanish, and four Chinese). Feasibility and acceptability were evaluated using phlebotomist and participant feedback following the encounter. We evaluated the reliability and validity of the TabCAT-BHA and AD plasma biomarkers (pTau-217, NfL, GFAP, Aβ42/40) collected in the home against data collected in-clinic by the ADRC (Figure 2).

RESULT: Forty-five participants completed the pathway (Mean[SD]age=69.2[9.7]; 69% female), including 24 who were cognitively unimpaired, 14 with MCI, and seven with dementia (Figure 1). The home pathway was feasible and acceptable for all 35 phlebotomists, who reported no challenges in 79% of encounters and minor challenges in 21%. Eighty percent of participants reported a preference for home-based assessment compared to in-clinic. Test-retest reliability of the TabCAT subtests across settings was excellent (Match, r = 0.85, p < 0.001; Birdwatch r = 0.82, p < 0.001; Figure 3). The ROC analysis for in-home TabCAT tasks after adjusting for sex, age, and education yielded an area under the curve (AUC) of 0.92 for separating cognitively impaired (i.e., MCI or dementia) from unimpaired, (95% CI: 0.81-0.99), with sensitivity of 0.85 and specificity of 0.95. At the time of this submission, plasma biomarker measurements are underway, and the results will be reported by July 2025.

CONCLUSION: This novel home-based pathway is a promising approach for the collection of digital cognitive assessments and ADRD plasma biomarkers, potentially aiding in early diagnosis and informing disease modifying treatment eligibility. Importantly, this pathway may also reduce barriers to testing and expanding access to dementia care.},
}

Humans
Female
Male
*Alzheimer Disease/diagnosis/blood
Aged
Biomarkers/blood
Reproducibility of Results
Neuropsychological Tests
Amyloid beta-Peptides/blood
Aged, 80 and over
Middle Aged
Feasibility Studies
*Cognitive Dysfunction/diagnosis

@article {pmid41448210,
year = {2025},
author = {Bukovsky, D and Amaev, A and Song, J and Torres-Carmona, E and Kyte, S and Ueno, F and Deluca, V and Bowie, CR and Flint, A and Husain, I and Graff-Guerrero, A and Gerretsen, P},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e101101},
doi = {10.1002/alz70859_101101},
pmid = {41448210},
issn = {1552-5279},
mesh = {Humans ; *Cognitive Dysfunction/drug therapy/diagnostic imaging ; Positron-Emission Tomography ; *Psilocybin/therapeutic use ; *Drug Development ; Double-Blind Method ; *Hallucinogens/therapeutic use ; Male ; *Brain/diagnostic imaging/drug effects ; Aged ; Female ; },
abstract = {BACKGROUND: Amnestic mild cognitive impairment (aMCI) is characterized by synaptic loss and cognitive decline and is considered a precursor to Alzheimer's Disease. Currently, there are no effective treatments for aMCI, and available treatments (i.e., cholinesterase inhibitors) do not appear to improve cognitive or functional outcomes. Psychedelics, including psilocybin, have regained interest for treatment of treatment-resistant neuropsychiatric disorders. Research suggests psilocybin's psychedelic and clinical effects may be due to interaction with the 5HT2A serotonin receptor (5HTA-R) in the brain. Cognitive impairments, such as memory decline, have been associated with lower 5HT2A-R density in the brain. Encouragingly, preclinical animal studies suggest that psilocybin may promote synaptogenesis in the brain, particularly in areas associated with learning and memory, likely through its interaction with the 5HT2A-R. Psilocybin may represent a novel treatment to counter neurodegenerative progression and consequently improve cognitive outcomes in patients with aMCI.

METHOD: The present double-blind, placebo-controlled randomized PET study will use the radioligand [[18]F]SynVesT to assess psilocybin's effect on synaptic density in the hippocampus and prefrontal cortex of patients with aMCI, and whether these changes are associated with improved cognitive outcomes. aMCI participants and sex-matched healthy controls will be randomized to receive either two doses of 25mg psilocybin or placebo one week apart. Participants will be monitored by a study physician and qualified therapist. PET scans are conducted pre- and one-week post-treatment. Clinical, safety, and neuropsychological assessments are done at baseline and 1-, 4-, and 12-weeks post-treatment. Safety measures include monitoring vital signs, suicidal ideation, and adverse events (AEs).

RESULT: Pilot data from two aMCI participants (Male% = 50%, mean age = 71.0(±3.0), mean baseline MOCA = 22(±3.0)) and three healthy controls (Male% = 67%, mean age = 66.3(±5.1); mean baseline MOCA = 27.7(±1.5)) is available. All participants completed study procedures without issue. Psilocybin was well tolerated, with no unexpected or serious AEs. All expected AEs resolved without sequelae. Expected AEs included dizziness (n=4) and altered perception (n=3). Blinding remains in effect.

CONCLUSION: The preliminary data suggest psilocybin is safe, well-tolerated, and can be feasibly investigated in a supervised medical setting in older adults as a prospective treatment for aMCI.},
}

Humans
*Cognitive Dysfunction/drug therapy/diagnostic imaging
Positron-Emission Tomography
*Psilocybin/therapeutic use
*Drug Development
Double-Blind Method
*Hallucinogens/therapeutic use
Male
*Brain/diagnostic imaging/drug effects
Aged
Female

@article {pmid41448207,
year = {2025},
author = {Lynch, SY and Wang, Y and Wang, D and Bachhav, S and Xiong, H and Boiser, J and Stage, E and Bannon, AW and Graff, O and Florian, H},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102775},
doi = {10.1002/alz70859_102775},
pmid = {41448207},
issn = {1552-5279},
mesh = {Humans ; Aged ; Male ; Female ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Middle Aged ; Double-Blind Method ; Aged, 80 and over ; Positron-Emission Tomography ; Amyloid beta-Peptides ; *Drug Development ; Dose-Response Relationship, Drug ; Brain/diagnostic imaging ; Treatment Outcome ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive, irreversible, fatal neurodegenerative disorder, and is the leading cause of dementia among the elderly population globally. ABBV-916 is a potential disease-modifying treatment for AD that targets Aβ peptides bearing a pyroglutamate residue at amino acid position 3, an Aβ species predominantly found in parenchymal amyloid plaques. This study aims to evaluate the efficacy, pharmacokinetics (PK) and safety of ABBV-916 in participants with early AD.

METHOD: This Phase 1b/2, multicenter, randomized, placebo-controlled, multiple ascending dose study included adults aged 50-90 years, with Stage 3 or 4 AD, a Mini-Mental State Examination score of 20-28, and a positive amyloid positron emission tomography (PET) scan ≥37 centiloids. Six cohorts with doses ranging from 10-3,000 mg were planned. Participants were randomized 3:1 to receive either ABBV-916 or placebo every 4 weeks (Q4W) intravenously over a 24-week double-blind period. Safety monitoring included adverse events (AE), clinical laboratory assessments, and magnetic resonance imaging scans. Dose escalation occurred only after the review of safety, PK and PET assessments (where available) by the safety committee.

RESULT: Preliminary results included 106 patients receiving doses from 10-2,000 mg, of which 74 had ≥1 post-baseline PET scan. After 24 weeks, PK exposures (maximum observed serum concentration [Cmax] and area under the curve [AUC0-D29]) were dose proportional across all doses, with low inter-subject variability (Figure 1). Treatment with ABBV-916 300 mg and 900 mg resulted in a dose-dependent brain amyloid reduction from baseline (Figure 2), with 60.0% and 85.7% of participants, respectively, achieving amyloid negativity at Week 24. Across all cohorts, AEs and serious AEs were reported by 61.3% and 6.6% of participants, respectively, and 12.3% of participants discontinued treatment due to AEs. No deaths occurred during the double-blind period. The incidences of amyloid-related imaging abnormalities-edema (ARIA-E) and hemosiderin deposition (ARIA-H) were 19.8% and 17.0%, respectively, and infusion-related reactions occurred in 6.6% of participants.

CONCLUSION: Preliminary data suggest that the safety and PK profile of ABBV-916 is comparable to currently approved anti-amyloid immunotherapies for the treatment of AD. Brain amyloid reduction was observed at doses of 300 mg or higher.},
}

Humans
Aged
Male
Female
*Alzheimer Disease/drug therapy/diagnostic imaging
Middle Aged
Double-Blind Method
Aged, 80 and over
Positron-Emission Tomography
Amyloid beta-Peptides
*Drug Development
Dose-Response Relationship, Drug
Brain/diagnostic imaging
Treatment Outcome

@article {pmid41448197,
year = {2025},
author = {Lancaster, CL and Dowell, N and Bakker, A and Bird, C and Tabet, N and Rusted, JM},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e100799},
doi = {10.1002/alz70859_100799},
pmid = {41448197},
issn = {1552-5279},
mesh = {Humans ; *Levetiracetam/therapeutic use ; Male ; Female ; Middle Aged ; Apolipoprotein E4/genetics ; Double-Blind Method ; Aged ; *Drug Development ; Genotype ; Neuropsychological Tests ; Alzheimer Disease/genetics/drug therapy ; *Executive Function/drug effects ; *Anticonvulsants/therapeutic use ; *Cognition/drug effects ; },
abstract = {BACKGROUND: Low-dose levetiracetam is under investigation as a potential treatment for slowing the progression of Alzheimer's Disease (AD). This commonly prescribed anti-seizure medication has, at low doses, been shown to downregulate excess neuronal activity - a prognostic risk marker observed in the earliest stages of AD, as well as in cognitively healthy carriers of the Apolipoprotein e4 (APOE4+) genetic risk variant. This study tests whether Levetiracetam has acute cognitive benefits in cognitively healthy mid-age adults, including whether drug effects differ by APOE4 genotype.

METHODS: Fifty-eight adults (aged 45-65 years old; 27 APOE33; 31 APOE4+) participated in a double-blind, placebo-controlled study of low-dose levetiracetam (125mg bidaily for two-weeks). At the end of each treatment phase (placebo, levetiracetam), participants completed an executive switch-inhibition task. Trial-level data was subject to generalised linear mixed effect modelling to estimate drug by genotype group differences in probability of correct response and response time (RT).

RESULTS: Independent of the effect of treatment, APOE4+ carriers showed poorer accuracy on trials requiring response inhibition (F(1, 15935)=12.39, p<.001), and slower RTs across all task trials (F(1, 15107)=12.15, p<.001). A significant interaction between drug condition and APOE4 status was reported for both probability of correct response (F(1, 15935)=32.19, p<.001) and RT (F1, 15107) = 25.64, p<.001). Levetiracetam treatment significantly enhanced performance accuracy (z-ratio = -3.05, p=.002) and RT (z-ratio = 7.98, p<.001) in APOE33 individuals, with greater beneficial effects of Levetiracetam on response speed observed with lower age. Levetiracetam treatment did not significantly affect probability of correct response or RT in APOE4+ individuals (p>.05).

CONCLUSION: Low-dose levetiracetam selectively enhanced executive function in mid-age APOE33 individuals, but did not modify performance in APOE4+ carriers, despite literature reporting brain hyperactivity in this at-risk group. Consistent with existing findings that an 18-month intervention with low-dose levetiracetam slows cognitive decline and brain atrophy in non-APOE4+ individuals with Mild Cognitive Impairment due to AD, this drug may be used prophylactically in those who don't carry an APOE4 risk variant. Ongoing future work must verify whether Levetiracetam modifies brain hyperactivity in APOE4+ individuals, and if so, what are the longer-term cognitive and neurological consequences of this intervention.},
}

Humans
*Levetiracetam/therapeutic use
Male
Female
Middle Aged
Apolipoprotein E4/genetics
Double-Blind Method
Aged
*Drug Development
Genotype
Neuropsychological Tests
Alzheimer Disease/genetics/drug therapy
*Executive Function/drug effects
*Anticonvulsants/therapeutic use
*Cognition/drug effects

@article {pmid41448196,
year = {2025},
author = {Kaye, JA and Speers, AB and Mar, AB and Marcoe, J and Mattek, N and Au-Yeung, WM and Beattie, ZT and Gothard, S and Hanna, EJ and Pierce, A and Silbert, LC and Shang, Y and Schwartz, D and Steele, JS and Thomas, CA and Wright, KM},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e106111},
doi = {10.1002/alz70859_106111},
pmid = {41448196},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy/diagnostic imaging/diagnosis ; Biomarkers ; Amyloid beta-Peptides/metabolism ; Positron-Emission Tomography ; Male ; *Drug Development ; Female ; Aged ; Disease Progression ; Prodromal Symptoms ; },
abstract = {BACKGROUND: Current conventional cognitive testing and self-report questionnaires used in clinical trials for Alzheimer's disease (AD) especially in prodromal early stages are poorly sensitive to detect subtle and gradual clinical change as well as lack ecological validity. Digital biomarkers (DBs) can detect salient change objectively, continuously and unobtrusively in real life settings, thus dramatically improving the conduct of clinical trials. Despite this promise there are few trial-focused studies conducted in the community that have provided evidence for how well continuously assessed, home-based digital biomarkers may detect clinically meaningful changes in individuals with changing amyloid (Aβ) burdens in pre-symptomatic and prodromal AD. DETECT-AD (ClinicalTrials.gov, NCT05385913) is a simulated clinical trial being conducted to create this evidence. Here we report the baseline results of the study.

METHOD: Clinically pre-symptomatic and prodromal AD patients with estimable rates of AD progression based on Aβ Florbetapir-PET status are enrolled and divided into n=50 Aβ "positive" (higher amyloid burden) patients who predictably progress (as if they were receiving placebo) and n=50 Aβ "negative" patients progressing more slowly (representing the treatment group). A study-provided multivitamin mimics trial conditions and study drug adherence behavior. Baseline standard clinical and biomarker measures are obtained along with DBs captured with passive and active sensors (actigraphy, bed mats, IR sensing, e-pillbox, computing device use, weekly online reporting/cognitive assessment). Primary outcome is the change in a composite DB composed of measures in 4 domains: mobility, cognition, sleep, and socialization. Secondary measures are the relationship of DBs to fluid biomarkers (plasma ptau181/217, amyloid, NfL), MRI, and PET measures.

RESULT: Full enrollment (n=103) was achieved (see Figure). Baseline clinical characteristics are presented in Table 1. Primary baseline DBs (average of 4 four weeks) are presented in Table 2. By design, differences were noted at baseline in SUVR. At baseline there were differences in age (2.8 years) and CDR SoB (0.1 points) in clinical characteristics. There were no differences in DBs during the baseline period.

CONCLUSION: Digital biomarkers can be integrated into anti-amyloid designed trials. Stable baseline DB measures between Aβ "negative" and "positive" patients sets the stage for sensitively observing divergent DB trajectories over time.},
}

Humans
*Alzheimer Disease/drug therapy/diagnostic imaging/diagnosis
Biomarkers
Amyloid beta-Peptides/metabolism
Positron-Emission Tomography
Male
*Drug Development
Female
Aged
Disease Progression
Prodromal Symptoms

@article {pmid41448189,
year = {2025},
author = {Kim, J and Ku, D and Park, I and Ye, S and Cho, I and Lee, S and Kim, I and Kim, Y},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e100127},
doi = {10.1002/alz70859_100127},
pmid = {41448189},
issn = {1552-5279},
mesh = {Animals ; *Amyloid beta-Peptides/metabolism ; *Alzheimer Disease/drug therapy ; Mice ; Disease Models, Animal ; *Drug Development ; Peptide Fragments ; Brain/drug effects/metabolism ; Humans ; Male ; },
abstract = {BACKGROUND: Abnormal accumulation of amyloid-β (Aβ) aggregates in the brain is a prominent pathology in Alzheimer's disease (AD). This phenomenon is strongly associated with cognitive deficits resulting from neuroinflammation and synaptic dysfunction. Recent studies in AD therapeutics development have highlighted the prospect of reducing amyloid burden in treating AD patients as a promising treatment strategy, prompting the development of small molecule drugs capable of inducing chemical dissociation and clearance of Aβ.

METHOD: Herein, we synthesized a chemical library of new chemical entities and selected a compound, IK-9j, that demonstrated profound Aβ clearance efficacy via thioflavin T assays and dot blot analyses. The potential therapeutic efficacy of IK-9j was evaluated utilizing an Aβ42-infused mouse model.

RESULT: The IK-9j-treated group exhibited significantly higher levels of short- and long-term memory compared to the non-treated group.

CONCLUSION: Collectively, these results underscore the potential of IK-9j as a novel small-molecule therapeutic to mitigate Aβ-associated cognitive deficits in AD.},
}

Animals
*Amyloid beta-Peptides/metabolism
*Alzheimer Disease/drug therapy
Mice
Disease Models, Animal
*Drug Development
Peptide Fragments
Brain/drug effects/metabolism
Humans
Male

@article {pmid41448166,
year = {2025},
author = {Mallinckrodt, C and Hendrix, SB and Hendrix, K and Dickson, SP},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e100008},
doi = {10.1002/alz70859_100008},
pmid = {41448166},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; *Drug Development ; Disease Progression ; Clinical Trials as Topic ; Research Design ; },
abstract = {BACKGROUND: The foundational statistical challenge faced in the past 25 years of Alzheimer's Disease (AD) research stems from the shift to longer duration trials in early disease stage patients from shorter duration trials in later disease stage patients. Although beginning a disease modifying treatment in early disease is best for patients, clinical trials in early-stage patients are problematic because disease progression is slow, and it is difficult for a treatment to slow progression much when there is not much progression to slow.

METHOD: We compare statistical methods from 25 years ago to current methods, and then conclude with an evaluation of future directions RESULTS: Twenty-five years ago, Statistical Analysis Plans for AD Clinical Trial used: 1) a primary analysis based on ANCOVA and simple, ad-hoc imputation of missing data (e.g., last observation carried forward); 2) objectives and endpoints were specified, but clear statements on exactly what was to be estimated were lacking; 3) sensitivity analyses to assess the robustness of assumptions were not clearly outlined. Today, we have 1) multiple, principled, analytic options that can be tailored to the situation; e.g., MMRM and disease progression models; 2) clarity in what is to be estimated (estimands) and handling of intercurrent events; 3) clarity in assumptions and in the sensitivity analyses to test robustness of inferences to invalid assumptions; 4) increased precision / power via innovative designs (Bayesian adaptive dose finding, escalating cohort, sample size re-estimation), optimized endpoints (composite or global statistical test), and principled analyses that together make informative Phase 2 trials in AD feasible; 5) reduced variability due to implementation of CDISC standard dataset structures; 6) results expressed as time saved and % slowing to understand the clinical relevance.

Although the focus of this presentation is on clinical trials, statisticians have and will need to continue contributing to all facets of drug development, including methods to help identify better drug candidates, AI and machine learning applications, risk prediction models, new diagnostics, and fluid and digital biomarker development and validation for surrogacy. With recently approved drugs, optimized designs for clinical trials of combination treatments will be needed.},
}

Humans
*Alzheimer Disease/drug therapy
*Drug Development
Disease Progression
Clinical Trials as Topic
Research Design

@article {pmid41448164,
year = {2025},
author = {Guo, M and Zhao, N and Yang, Q and Fan, F},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e100207},
doi = {10.1002/alz70858_100207},
pmid = {41448164},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; Activities of Daily Living ; *Alzheimer Disease/surgery/psychology ; Mental Status and Dementia Tests ; Aged, 80 and over ; *Lymphatic Vessels/surgery ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder with no cure. AD is characterized by the pathological accumulation of Aβ plaques and hyperphosphorylated tau proteins. Recent studies have found that the lymphatic system plays a crucial role in the clearance of Aβ and tau. The present study seeks to explore whether deep cervical lymph-venous anastomosis (LVA), a surgery that was initially for the treatment of cervical lymphatic obstruction, has beneficial effects in AD patients.

METHODS: This study included 65 AD patients who met the 2024 diagnostic criteria and were in stages 4 to 6 of the disease, determined by the Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), and Activities of Daily Living (ADL). After anesthesia, indocyanine green (10 mM, 0.1 mL) was injected submucosally into the bilateral middle nasal turbinate to visualize deep cervical lymphatic vessels. The internal jugular vein was exposed, and fluorescently highlighted adjacent lymph nodes were carefully selected. Two-thirds of the lymph nodes were excised, while the remaining portion was anastomosed end-to-side with the internal jugular vein. A drainage tube was placed and removed on postoperative day 1. The procedure was performed bilaterally. MoCA, MMSE, and ADL were assessed on days 7 and at 3, 6, and 12 months post-operation and compared to preoperative baselines.

RESULTS: In 65 deep cervical LVA AD cases, nearly 90% showed overall improvements in cognition, daily living abilities, and quality of life. By postoperative day 7, most patients exhibited cognitive improvement accompanied by excitement, insomnia, or irritability. By postoperative 3 months, cognitive function and daily living abilities had all significantly improved. Ongoing studies are continuing to track longer-term outcomes.

CONCLUSION: The present study provided strong evidence demonstrating that deep cervical LVA improves cognitive function, mental state, and daily activities in AD patients. Our results suggest that this surgical procedure offers a promising therapeutic approach for AD treatment and paves the way for further investigation into its long-term consequences and underlying mechanisms.},
}

Humans
Male
Female
Aged
Activities of Daily Living
*Alzheimer Disease/surgery/psychology
Mental Status and Dementia Tests
Aged, 80 and over
*Lymphatic Vessels/surgery
Neuropsychological Tests

@article {pmid41448158,
year = {2025},
author = {Lu, W and Caulfield, TR and Jeevaratnam, S and Bu, G and Kanekiyo, T and Li, Y},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e100859},
doi = {10.1002/alz70859_100859},
pmid = {41448158},
issn = {1552-5279},
mesh = {Humans ; *Drug Development ; *Histone Deacetylase Inhibitors/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; *Wnt Signaling Pathway/drug effects ; Organoids/drug effects ; Induced Pluripotent Stem Cells/drug effects ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a multifactorial disease often with mixed pathologies. As such, drugs targeting multiple pathological processes simultaneously could have synergistic therapeutic effects. The histone acetylation homeostasis is greatly impaired in AD, and histone deacetylase (HDAC) inhibitors have been known to alleviate AD-relevant pathologies in various animal models. In addition, Wnt/β-catenin signaling is compromised in AD, and restoring Wnt/β-catenin signaling is an attractive therapeutic strategy for AD treatment. CI-994 is a class I HDAC inhibitor containing N-(2-aminophenyl)-benzamide. Our recent studies indicate that CI-994 is also an activator of Wnt/β-catenin signaling by stabilizing Wnt co-receptor LRP6.

METHOD: We use CI-994 as a scaffold to develop novel potent dual modulators for class I HDAC inhibition and Wnt/β-catenin signaling activation, and then determine the therapeutic potential of the lead compound W2A-28 in AD patient-specific iPSC-derived cerebral organoids.

RESULT: W2A-28 inhibits class I HDAC1, 2 and 3 activities with IC50 values of 512 nM, 675 nM and 217 nM, respectively, with no inhibitory activities on other HDACs and Sirtuin family members. Furthermore, W2A-28 greatly increases Wnt reporter activity with an EC50 value of 1.61 µM in Wnt-3A-expressing HEK293 cells. As expected, activation of Wnt/β-catenin signaling by W2A-28 is associated with elevated Wnt co-receptor LRP6 protein level by reducing LRP6 degradation. Importantly, W2A-28 displays excellent aqueous solubility and microsomal stability. Further, W2A-28 shows high permeability with no active efflux in MDR1-MDCKII permeability assays and is not a P-gp substrate. Finally, W2A-28 significantly reduces Aβ40 and Aβ42 levels and suppresses tau phosphorylation in AD patient-specific iPSC-derived cerebral organoids carrying APOE4.

CONCLUSION: Our studies suggest that W2A-28 is a potential drug candidate for the treatment of AD.},
}

Humans
*Drug Development
*Histone Deacetylase Inhibitors/pharmacology
*Alzheimer Disease/drug therapy/metabolism
*Wnt Signaling Pathway/drug effects
Organoids/drug effects
Induced Pluripotent Stem Cells/drug effects

@article {pmid41448156,
year = {2025},
author = {Sherif, HM and Clark, LR and Chin, NA and Hartley, SL and Christian, BT and Ketchum, FB},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e100947},
doi = {10.1002/alz70858_100947},
pmid = {41448156},
issn = {1552-5279},
mesh = {Humans ; *Caregivers/psychology ; *Down Syndrome/psychology/complications ; *Disclosure ; Biomarkers ; Adult ; *Alzheimer Disease/diagnostic imaging/psychology ; *Dementia/psychology ; Positron-Emission Tomography ; Female ; Male ; },
abstract = {BACKGROUND: Adults with Down Syndrome (DS) have a greater than 90% lifetime risk of developing dementia due to Alzheimer's Disease (AD). There is an urgent need for clinical trials in this population, which will require biomarker testing and disclosure of results. Disclosure protocols have been widely used for neurotypical individuals. However, effective approaches to disclosure may differ between neurotypical adults at risk for late-onset AD, and adults with DS who are typically part of a patient-caregiver dyad with a unique psychosocial context. We developed a protocol to disclose amyloid PET biomarker results for adults with DS and their caregivers participating in the Alzheimer Biomarker Consortium Down Syndrome (ABC-DS) study.

METHOD: We adapted a disclosure toolkit that has been extensively tested in longitudinal studies for amyloid PET biomarker disclosure to neurotypical adults. We first identified the unique needs of dyads around disclosure through a literature review and consultations with experts in DS, intellectual and developmental disabilities (IDDs), and AD clinical care. We created a protocol encompassing screening, education, results disclosure, and post-disclosure check-in.

RESULT: Adults with DS are often supported by family caregiver(s), who face challenges including lack of awareness of the increased risk of developing AD, difficulty in obtaining a timely diagnosis, limited resources for psychosocial support, and lack of access to clinical trials. We adapted materials to address the informational needs of dyads and adapted the disclosure protocol to focus on and assess the following: level of understanding of the biomarker results, concerns, and capacity to act on disclosure results and seek resources. Specific training was also provided to disclosing clinicians on the diagnosis of AD in adults with DS.

CONCLUSION: To our knowledge this is the first adaptation of an amyloid PET disclosure protocol for adults with DS and their caregivers. This adaptation emphasizes empowering the dyad, and is a first step towards achieving equity in AD diagnosis and treatment for a population of individuals with Down Syndrome. In the next phase of research, we will further refine the protocol through pilot testing with adults with DS who have undergone amyloid PET scans as part of ABC-DS.},
}

Humans
*Caregivers/psychology
*Down Syndrome/psychology/complications
*Disclosure
Biomarkers
Adult
*Alzheimer Disease/diagnostic imaging/psychology
*Dementia/psychology
Positron-Emission Tomography
Female
Male

@article {pmid41448149,
year = {2025},
author = {Kim, Y and Han, SH and Lee, H and Chun, YS and Kim, SM and Kim, HJ and Park, SJ},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e100122},
doi = {10.1002/alz70859_100122},
pmid = {41448149},
issn = {1552-5279},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Animals ; Humans ; *Drug Development ; *Amyloid beta-Peptides/metabolism/drug effects ; *tau Proteins/metabolism/drug effects ; Mice ; Plaque, Amyloid/drug therapy ; Disease Models, Animal ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques and tau tangles, key therapeutic targets. While immunotherapies have been developed to clear Aβ or tau aggregates individually, no strategy has simultaneously targeted both. AS-S603, a novel small molecule in clinical trial phase 1 (NCT06786676), is designed to chemically clear Aβ and tau aggregates, including plaques, tangles, and oligomers, by dissociating them into monomers and preventing further aggregation.

METHOD: AS-S603 was discovered through an unbiased high-throughput screening, a proprietary assay system designed to identify molecules that dissociate misfolded proteins from over 50,000 compounds targeting Aβ and tau aggregates. Hits were optimized through iterative derivatization to the final candidate. Comparative studies with Lecanemab, ALZ-801, and TRx0237 in aged 5xFAD and PS19 mice highlighted its efficacy, including behavioral improvements in Morris Water Maze tests and amyloid clearance imaging with amyloid-PET using 18F-fluorobetaben. Novel tools were developed to investigate its mode of action (MoA), revealing how AS-S603 dissociates oligomers, plaques, and tangles with specificity to Aβ and tau. Non-clinical studies confirmed its tolerability and clinical readiness. For clinical trials, AS-S603 was developed in a once-daily tablet.

RESULT: AS-S603 dissociates Aβ and tau aggregates, converting both soluble oligomers and insoluble plaques and tangles into monomers. It targets extracellular and intracellular aggregates, broadening its therapeutic scope. In preclinical studies, AS-S603 showed significantly improved cognitive benefits compared to Lecanemab at both 1 mpk and 10 mpk. Amyloid-PET scans revealed a more substantial reduction in amyloid burden for AS-S603. Biophysical, biochemical, and molecular docking simulation studies revealed its MoA, showing that AS-S603 binds to the hydrophobic pocket of Aβ and tau, disrupting hydrogen bonding and inducing dissociation. Binding assays showed no off-target effects. Blood-brain barrier penetration of AS-S603 is over 200%, demonstrating an advantage over antibodies. Safety evaluations confirmed a favorable tolerability profile. The Phase 1 clinical trial is currently underway.

CONCLUSION: AS-S603 is a first-in-class oral treatment for AD, uniquely targeting both Aβ and tau aggregates. It provides significant cognitive benefits in preclinical studies, suggesting its potential to alter disease progression. Clinical studies will validate its safety and efficacy, positioning AS-S603 as a transformative treatment for AD.},
}

*Alzheimer Disease/drug therapy/metabolism
Animals
Humans
*Drug Development
*Amyloid beta-Peptides/metabolism/drug effects
*tau Proteins/metabolism/drug effects
Mice
Plaque, Amyloid/drug therapy
Disease Models, Animal

@article {pmid41448145,
year = {2025},
author = {Fargo, KN and Armstrong, MJ and Bauer, LJ and Boeve, BF and Galvin, JE and Sabbagh, MN and Valentine, JE and Fazio, S and Laurence, G and Levine, B and Medsger, HB and Neumann, LTV and Pfleeger, K and Pugh, G and Rachchh, E and Stokes, J and Walter, D and Taylor, AS},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e104394},
doi = {10.1002/alz70859_104394},
pmid = {41448145},
issn = {1552-5279},
mesh = {Humans ; *Drug Development ; *Lewy Body Disease/drug therapy/psychology ; United States ; United States Food and Drug Administration ; },
abstract = {BACKGROUND: Dementia with Lewy bodies (DLB) is a prevalent form of dementia associated with neuronal alpha-synuclein aggregates (Lewy bodies). Symptoms include cognitive impairment, fluctuations, neuropsychiatric features including psychosis, sleep disorders, and dysautonomia. DLB is the most expensive form of dementia, and there are currently no treatments approved by the US FDA. Given the advent of sensitive and specific in vivo biomarkers for synuclein aggregation, drug developers are increasingly interested in DLB. FDA instituted Patient-Focused Drug Development (PFDD) meetings in 2012 with the purpose of ensuring that patients' experiences, perspectives, needs, and preferences are captured and meaningfully incorporated into drug development and evaluation.

METHOD: In October 2024, the Lewy Body Dementia Association (LBDA) and the Alzheimer's Association (ALZ) co-hosted an externally-led PFDD (EL-PFDD) meeting on DLB. Thirty days before the event, LBDA solicited public comment on the lived experience of DLB, the current state of treatment, and what people with DLB value in potential future therapies. During the live meeting, people with DLB, care partners and family members described their experiences and responded to live polling questions.

RESULT: The EL-PFDD was attended by 347 people with DLB and care partners, drug developers (both industry and academic), FDA staff, and NIH staff. Preliminary analysis of the discussion content and survey responses shows several themes emerging from the meeting. The most bothersome and impactful symptoms varied over the course of the disease, but included cognitive impairment and fluctuations, neuropsychiatric symptoms, and sleepiness. Concerns for the future included progressive decline in cognition, changes in behavior/mood, and cost of care. Limitations to current treatments included lack of FDA-approved medications, and side effects and lack of efficacy associated with "off label" medications. Priorities for future treatments included symptomatic treatments that do not worsen other DLB symptoms, slowing disease progression, accessibility/insurance coverage, and avoiding side effects.

CONCLUSION: The EL-PFDD on DLB provided valuable information for drug developers and regulators to understand the lived experience of people with DLB and care partners. The results will be documented in a "Voice of the Patient" report that will be hosted at www.lbda.org/el-pfdd.},
}

Humans
*Drug Development
*Lewy Body Disease/drug therapy/psychology
United States
United States Food and Drug Administration

@article {pmid41448129,
year = {2025},
author = {Kujuro, Y},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e100084},
doi = {10.1002/alz70859_100084},
pmid = {41448129},
issn = {1552-5279},
mesh = {Humans ; Retrospective Studies ; *Cognitive Dysfunction/drug therapy ; Female ; Male ; *Alzheimer Disease/drug therapy ; Aged ; *Drug Development ; Aged, 80 and over ; Japan ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Middle Aged ; Neuropsychological Tests ; },
abstract = {BACKGROUND: Since the approval of Lecanemab in Japan on September 25, 2023, for mild cognitive impairment (MCI) and mild dementia due to Alzheimer's disease (AD), the number of dementia-related phone inquiries at our hospital has increased by 1.7 times over a period of 6 months (from 457 inquiries before to 759 inquiries after). Due to the public health insurance system and the high-cost medical expense system in Japan, patients have equal access to Lecanemab treatment. We will present how we have prepared our outpatient services, our experience with using the drug, and the arrangements for continued administration after 6 months.

METHOD: We conducted a retrospective data analysis of 58 patients who were treated with Lecanemab between January and December 2024 at our Center for Dementia-Related Diseases in Tokyo. All patients have been confirmed to be amyloid pathology positive by either cerebrospinal fluid (CSF) or amyloid PET.

RESULT: 82% of the patients who started Lecanemab were referred by general practitioners, and 40% of those referrals specifically requested consideration of Lecanemab treatment. After scheduling an outpatient appointment, a head MRI and neuropsychological tests were performed at our facility before the first medical examination. Clinical characteristics of patients treated with Lecanemab were as follows: age at 1st Lecanemab infusion 76.2±8.5 years (54-92 years), 69% female, 96.6% Japanese (1.7% Chinese, 1.7% Korean), MMSE 24.6±2.0 (22-30), CDR-J 0.5: 92%, and 1: 8%, CSF Aβ42/Aβ40 ratio 0.049±0.009, Amyloid PET Centiloid scale 75.2±21.1. None of the patients had amyloid-related imaging abnormalities (ARIA) -E, 6.9% had ARIA-H (5.2% asymptomatic mild, 1.7% asymptomatic moderate), 1.7% had mild infusion reaction. Following the initial 6 months of Lecanemab administration, continuous infusions can be carried out at facilities that meet certain criteria. Consequently, we have referred 11 patients to other facilities.

CONCLUSION: Consistent with prior evidence, Asian patients tend to have less ARIA side effects. Due to the high demand of Lecanemab treatment, it is necessary to promptly refer patients to continuous administration facilities after the initial 6 months of administration.},
}

Humans
Retrospective Studies
*Cognitive Dysfunction/drug therapy
Female
Male
*Alzheimer Disease/drug therapy
Aged
*Drug Development
Aged, 80 and over
Japan
*Antibodies, Monoclonal, Humanized/therapeutic use
Middle Aged
Neuropsychological Tests

@article {pmid41447791,
year = {2025},
author = {Natalya, Y and Hadad, R and Heller, I and Kapon, L and Kogan, O and Levavi, M and Shor, M and Manov, N and Fisher, T and Aharon-Peretz, J and Tanne, D and Ben-Hayun, R},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e101653},
doi = {10.1002/alz70856_101653},
pmid = {41447791},
issn = {1552-5279},
mesh = {Humans ; Female ; *Biomarkers/cerebrospinal fluid ; Male ; Middle Aged ; *Cognitive Dysfunction/cerebrospinal fluid/diagnosis ; *Alzheimer Disease/cerebrospinal fluid/diagnosis ; tau Proteins/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Aged ; Spinal Puncture ; Diagnosis, Differential ; },
abstract = {BACKGROUND: An accurate clinico-biological diagnosis of cognitive decline is crucial for identifying neurodegenerative diseases from disorders with similar clinical presentations and administration of appropriate treatments. Recent biotechnological advancements have enabled the measurement of protein biomarkers associated with Alzheimer's Disease (AD) pathology and the assessment of paraneoplastic and non-paraneoplastic antibodies indicative of autoimmune processes. Since June 2020, our service has conducted comprehensive assessments, incorporating neurological, cognitive evaluations, imaging and CSF biomarker workups. Our aim was to assess the effectiveness of our approach in achieving an accurate clinic-biological diagnosis of the underlying etiology of cognitive impairment in individuals evaluated at our center.

METHOD: Consenting patients presenting with cognitive and/or behavioral deterioration underwent lumbar puncture (LP) for cerebrospinal fluid (CSF) analysis, tailored according to the clinical differential diagnosis. The analysis included cell count, protein, glucose, chloride, cytology, AD biomarkers-total tau, 181-phosphorylated tau, amyloid-β42-and panels for paraneoplastic and non-paraneoplastic antibodies.

RESULT: A total of 131 patients presenting with cognitive and/or behavioral deterioration (mean age 63.4 ± 9.4 years; 60 females, 45%) underwent LP for CSF evaluation. AD biomarkers were assessed in 120 subjects, with 59 (49%) testing positive. Antibodies associated with autoimmune encephalitis were tested in 92 subjects, revealing positive paraneoplastic antibody profiles in 14 (15%) subjects (8 with biomarker-confirmed AD and 6 with non-AD pathology). Two patients with positive both AD-biomarkers and paraneoplastic antibodies passed away 34 and 77 months after the evaluation, 6 received immune treatment, and 5 were diagnosed with an oncological condition.

CONCLUSION: Our study highlights the significant value of biomarkers in diagnosing cognitive and behavioral impairments, helping to prevent misdiagnosis or inappropriate labeling of Alzheimer's Disease and guiding the appropriate treatment. We suggest that it is essential to include autoimmune encephalopathy in the differential diagnosis for patients presenting with cognitive decline, as appropriate treatment can be life-saving.},
}

Humans
Female
*Biomarkers/cerebrospinal fluid
Male
Middle Aged
*Cognitive Dysfunction/cerebrospinal fluid/diagnosis
*Alzheimer Disease/cerebrospinal fluid/diagnosis
tau Proteins/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
Aged
Spinal Puncture
Diagnosis, Differential

@article {pmid41447790,
year = {2025},
author = {Abraham, R and Goura, V and Kallepalli, R and Medapati, RB and Varalakshmi, O and Bojja, K and Shaikh, A and Badange, RK and Manchineella, S and Narasimhula, T and Das, A and Guduru, NSSCS and Bitra, KS and Mukkollu, KS and Nissankarao, MP and Pandey, SK and Goyal, VK and Nirogi, R},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e100081},
doi = {10.1002/alz70859_100081},
pmid = {41447790},
issn = {1552-5279},
mesh = {Animals ; *Drug Development ; Humans ; *Alzheimer Disease/drug therapy ; Male ; *Muscarinic Agonists/pharmacology ; Receptor, Muscarinic M4/agonists ; Rats ; Nortropanes/pharmacology ; Pyridines ; Thiadiazoles ; },
abstract = {BACKGROUND: Neuropsychiatric symptoms (NPS) associated with Alzheimer's disease (AD) are burdensome to the caregiver and patients. The current therapies for the treatment of NPS in AD are associated with limited efficacy and severe side effects. Hence, newer treatment options are required to effectively control these symptoms. The combination of xanomeline and trospium (KarXT) has recently been approved for the treatment of schizophrenia and has been proposed for the treatment of NPS associated with AD as well. Xanomeline, a muscarinic M1/M4 agonist, is likely to induce peripheral side effects. To overcome peripheral side effects, trospium, a peripheral anticholinergic agent, is administered with xanomeline. Since positive allosteric modulators (PAMs) act on the allosteric site rather than the orthosteric site, they are less likely to induce peripheral side effects. Here, we present the safety and pharmacodynamics properties of an M4 PAM, SUVN-L3307032.

METHOD: The in-vitro properties of SUVN-L3307032 were characterized. Its effect on the allosteric site of the muscarinic M4 receptors was characterized using reporter gene assay. The efficacy of SUVN-L3307032 was assessed in an amphetamine induced hyperlocomotion test using an open field. Receptor occupancy of SUVN-L3307032 was assessed using non-radiolabeled based method. SUVN-L3307032 was assessed for its efficacy to reverse hallucinations induced by 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) by assessing head twitch responses. Efficacy of SUVN-L3307032 in reversing cognitive deficits associated with psychiatric symptoms was assessed in a fear conditioning task. Preliminary toxicity studies were conducted in rats and dogs to evaluate the safety of SUVN-L3307032.

RESULT: SUVN-L3307032 was found to be a selective M4-PAM. SUVN-L3307032 attenuated amphetamine induced hyperlocomotion in an open field test. In the fear conditioning task, SUVN-L3307032 reversed amphetamine induced cognitive deficits. SUVN-L3307032 attenuated head twitch responses induced by DOI. The observations from the amphetamine-induced hyperlocomotion assay correlated well with the occupancy at the allosteric site of muscarinic M4 receptors. Preliminary toxicity studies did not show any concerns for further development.

CONCLUSION: SUVN-L3307032 has the potential to be a new therapeutic option for the treatment of NPS associated with AD.},
}

Animals
*Drug Development
Humans
*Alzheimer Disease/drug therapy
Male
*Muscarinic Agonists/pharmacology
Receptor, Muscarinic M4/agonists
Rats
Nortropanes/pharmacology
Pyridines
Thiadiazoles

@article {pmid41447732,
year = {2025},
author = {Showell, S and Gillis, C and Powell, L},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e101136},
doi = {10.1002/alz70858_101136},
pmid = {41447732},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; Aged ; *Alzheimer Disease/epidemiology/therapy/psychology ; *Health Services Accessibility/statistics & numerical data ; United States ; Aged, 80 and over ; *Healthcare Disparities ; Cognitive Dysfunction/epidemiology ; Hispanic or Latino ; White ; },
abstract = {BACKGROUND: Recent advances in Alzheimer's disease (AD) treatment include approval of two amyloid directed immunotherapies administered via intravenous infusion. These therapies require access to infusion centers, making availability of such facilities critical for effective treatment delivery. We examined accessibility of infusion centers across three cities in the United States. Our analyses aimed to identify patients with limited access to treatment and assess whether these gaps align with known disparities in Alzheimer's disease.

METHOD: Three large metropolitan areas (Atlanta, GA; Chicago, IL; Houston, TX) with ethnic (>20% Hispanic/Latino) and/or racial diversity (>45% non-white) were selected to examine characteristics of residents living in infusion deserts (IDs). The National Infusion Center Association Locator Data was used to examine gaps in availability at the neighborhood/census tract level with an ID defined as an area where the closest infusion center >5 miles radius. Demographic characteristics were compared between IDs and non-IDs using CDC PLACES data. To estimate the number of 65+ years amyloid-positive (Aβ+) MCI due to AD and mild AD individuals in an infusion desert, we applied estimates of MCI/AD prevalence, AD severity, and amyloid abnormality to the estimates of those 65+ living in an ID.

RESULT: Across three US metropolitan areas, approximately 12% of the population live in an ID. Among people 65+ years, approximately 18k living with Aβ+ MCI due to AD and 8k living with Aβ+ mild AD resides in an ID in one of these three cities (Table 1). IDs showed a higher proportion of Hispanic/Latino residents compared to non-IDs, ranging from 1% higher in Atlanta to 12% higher in Houston. A higher proportion of Black/African American individuals and a lower proportion of White and Asian individuals reside in an ID compared to non-ID areas. Differences in the proportion of Black/African American race between ID and non-IDs ranged from 7.7% higher in ID for Houston to 42.8% higher in Atlanta (Table 2).

CONCLUSION: Approximately 26k individuals 65+ years with Aβ+ early AD are living in an ID across Atlanta, Chicago, and Houston. Locations of IDs are disproportionately Black/African American and Hispanic/Latino compared to non-IDs, suggesting potential inequalities in access to new treatments for AD.},
}

Humans
Female
Male
Aged
*Alzheimer Disease/epidemiology/therapy/psychology
*Health Services Accessibility/statistics & numerical data
United States
Aged, 80 and over
*Healthcare Disparities
Cognitive Dysfunction/epidemiology
Hispanic or Latino
White

@article {pmid41447730,
year = {2025},
author = {Wang, HJJ and Ruthirakuhan, M and Herrmann, N and Andreazza, AC and Gallagher, D and Verhoeff, NPLG and Kiss, A and Black, SE and Feldman, OJ and Lanctôt, KL},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e103580},
doi = {10.1002/alz70857_103580},
pmid = {41447730},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/complications/drug therapy/blood ; Biomarkers/blood ; Aged ; *Psychomotor Agitation/drug therapy/etiology/blood ; Cross-Over Studies ; Aged, 80 and over ; },
abstract = {BACKGROUND: Agitation is a challenging neuropsychiatric symptom (NPS) of Alzheimer's disease (AD). A crossover trial found that nabilone significantly improved agitation in AD patients over 6 weeks compared to placebo. Here, we aim to identify a combination of biomarkers that could be used to predict treatment response to nabilone for AD-associated agitation.

METHODS: Agitation was assessed using the Cohen-Mansfield Agitation Inventory (CMAI). Serum concentrations of 13 markers were measured. Linear regression was used to estimate change in CMAI due to nabilone for the high and low groups of each biomarker. Biomarkers with a difference ≥8.5 points between groups were included in subsequent multivariate models. Index scores representing the difference between expected CMAI change given nabilone and placebo were calculated and divided into quartiles. Mean difference in CMAI change and 95% confidence intervals were estimated via bootstrapping.

RESULTS: Four of the 13 biomarkers which met criteria specified above were included in multivariate modeling (n = 67). Nabilone was more efficacious in participants with higher IL-6 (estimated change in CMAI -15.4, standard error (SE) 5.6), higher ISO-8 (-14.4, SE=5.0), higher 24S-OHC (-14.2, SE=4.1), and lower clusterin (-14.6, SE=4.4). Participants in Q1 of index scores demonstrated better response to nabilone with a mean difference in CMAI change of -20.9 (95% CI: -31.8, -9.2), while those in Q2-4 showed no difference between treatments.

CONCLUSIONS: Participants with higher levels of inflammation, oxidative stress, and cholesterol metabolite were more likely to benefit from nabilone for agitation in AD. A combination of biomarkers could help in distinguishing responders and non-responders to nabilone.},
}

Humans
Male
Female
*Alzheimer Disease/complications/drug therapy/blood
Biomarkers/blood
Aged
*Psychomotor Agitation/drug therapy/etiology/blood
Cross-Over Studies
Aged, 80 and over

@article {pmid41447717,
year = {2025},
author = {Kajal, K and Thakur, S and Deshmukh, RR},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e100123},
doi = {10.1002/alz70858_100123},
pmid = {41447717},
issn = {1552-5279},
mesh = {Animals ; Oxidative Stress/drug effects ; Rats ; *Fingolimod Hydrochloride/pharmacology/therapeutic use ; Male ; *Dementia/chemically induced/drug therapy/psychology/pathology ; Colchicine ; Rats, Wistar ; Disease Models, Animal ; *Neuroprotective Agents/pharmacology/therapeutic use ; Hippocampus/drug effects/pathology/metabolism ; Maze Learning/drug effects ; },
abstract = {Alzheimer's disease (AD) is an age related neurodegenerative disease which is mainly characterized by progressive cognitive decline, synaptic loss, extracellular amyloid-beta (Aβ) deposits and intracellular accumulation of neurofibrillary tangles of tau protein. Multiple etiological factors have been linked with AD pathophysiology, oxidative stress, neuroinflammation, neurotransmitter deficit and foremost are the deregulation of lipid metabolism, consistently involve in AD pathology and cognitive deficit. In the present study we have explored the neuroprotective potential of Fingolimod (FTY720), against intracerebroventricular colchicine (ICV-COL) induced experimental sporadic dementia in rats. COL was administered bilaterally at a dose of (15μg/rat) on the first day. Spatial and non-spatial memory was evaluated by using Morris water maze and object recognition test. Locomotor activity was evaluated by using open field test. Fingolimod (0.25 and 0.5 mg)/kg, p.o.) was administered on alternate days from 8th day after ICV -infusion in rats. The parameters of oxidative stress were accessed by measuring the malondialdehyde, reduced glutathione and catalase levels in the hippocampus and cortex region. ICV-COL infusion in rats produced cognitive deficit and caused significant elevation in markers and oxidative stress and degenerative changes in hippocampus and cortical brain region. On the contrary, Fingolimod treatment attenuate COL-induced cognitive decline, reduced oxidative burden and able to preserve the neuronal architecture and prevent neuronal loss in hippocampus and cortical brain region of the rats. The neurodegeneration in hippocampus and cortex regions was observed through histopathological examination. The outcome of the present study clearly indicates that the neuroprotective potential of fingolimod and suggesting its therapeutic potential in cognitive disorders.},
}

Animals
Oxidative Stress/drug effects
Rats
*Fingolimod Hydrochloride/pharmacology/therapeutic use
Male
*Dementia/chemically induced/drug therapy/psychology/pathology
Colchicine
Rats, Wistar
Disease Models, Animal
*Neuroprotective Agents/pharmacology/therapeutic use
Hippocampus/drug effects/pathology/metabolism
Maze Learning/drug effects

@article {pmid41447712,
year = {2025},
author = {Zhou, J and Andreozzi, E and Llibre-Guerra, JJ and Clifford, DB and Li, D and Wang, G and Schneider, LSS and McDade, E and Reyderman, L and Bateman, RJ},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e105304},
doi = {10.1002/alz70859_105304},
pmid = {41447712},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics ; *Drug Development ; Double-Blind Method ; Male ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use ; tau Proteins ; Middle Aged ; Aged ; },
abstract = {BACKGROUND: The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trial is an adaptive platform trial evaluating various therapies intended to slow or prevent the Alzheimer disease (AD) progression in Dominantly Inherited Alzheimer's disease (DIAD). In the Tau NexGen DIAN-TU-001 arm, the potential benefits of the anti-tau therapy etalanetug (E2814), a novel monoclonal antibody that binds to the MTBR, are being investigated with the anti-amyloid treatment lecanemab given as background therapy. While lecanemab has been shown to be well tolerated in multiple clinical trials, known risks include amyloid-related imaging abnormalities (ARIA) and infusion reactions. Herein, we provide an overview of 6-month safety results for DIAD participants in the symptomatic cohort (CDR 0.5-1, n=97) receiving lecanemab only in the Tau NexGen DIAN-TU-001 Trial.

METHODS: DIAN-TU-001 is a phase II/III multicenter randomized, double-blind, placebo-controlled platform trial of potential disease modifying therapies utilizing biomarker, cognitive, and clinical endpoints in DIAD. Safety evaluations included monitoring of vital signs, physical examinations, adverse events, clinical laboratory parameters, and 12-lead electrocardiograms. ARIA occurrence was monitored throughout the study by MRI, read both locally and centrally.

PRELIMINARY RESULTS: Lecanemab was generally well-tolerated during the 6-month lecanemab-only treatment period. Overall, 80.4% of the 97 participants enrolled and treated experienced an adverse event. The most common AEs were ARIA-H (26.8%), headache (25.8%), ARIA-E (20.6%), and infusion-related reactions (11.3%). The incidence of ARIA-E was 20.6% and the incidence of ARIA-H was 26.8%. The rate of symptomatic ARIA-E was 4.1% and symptomatic ARIA-H was 1.0%. ARIA-E most commonly occurred within the first 3 months of treatment (80.0%) and resolved within 4 months (75%). There were no cases of symptomatic isolated ARIA-H, no intracerebral hemorrhage (>10 mm), and 2 (2.06%) individuals who experienced ARIA leading to lecanemab withdrawal. The majority AEs were mild or moderate, with a total of 6 (6.19%) participants experiencing a serious AE.

CONCLUSIONS: Lecanemab was generally well-tolerated. The most common adverse events of lecanemab in the DIAD population were ARIA-H, headache, ARIA-E, and infusion-related reactions. DIAD population may have a higher rate of cerebral amyloid angiopathy with ARIA rates between heterozygotes and homozygotes in sporadic AD.},
}

Humans
*Alzheimer Disease/drug therapy/genetics
*Drug Development
Double-Blind Method
Male
Female
*Antibodies, Monoclonal, Humanized/therapeutic use
tau Proteins
Middle Aged
Aged

@article {pmid41447705,
year = {2025},
author = {Chen, Y and Mao, Z},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e101808},
doi = {10.1002/alz70856_101808},
pmid = {41447705},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/cerebrospinal fluid/pathology/diagnostic imaging/diagnosis ; Amyloid beta-Peptides/cerebrospinal fluid ; tau Proteins/cerebrospinal fluid ; Aged ; *LIM Domain Proteins/cerebrospinal fluid ; Positron-Emission Tomography ; Cross-Sectional Studies ; Brain/pathology ; *Adaptor Proteins, Signal Transducing/cerebrospinal fluid ; Cognitive Dysfunction/pathology/cerebrospinal fluid ; Aged, 80 and over ; Longitudinal Studies ; },
abstract = {BACKGROUND: LIM-domain-only 4 (LMO4) is involved in neurodevelopment and synaptic plasticity, but its role in the pathogenesis of Alzheimer's disease (AD) remains unclear.

METHOD: We included 703 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Associations between CSF LMO4 and AD biomarkers (Aβ42, Ptau181, amyloid PET) and postmortem neuropathology were evaluated. Cross-sectional and longitudinal associations between CSF LMO4 and neurodegeneration and cognitive function were explored. Receiver operating characteristic analysis assessed the diagnostic accuracy of CSF LMO4 in distinguishing Aβ-positive from Aβ-negative participants and amyloid PET-confirmed AD cases. Mediation analysis explored the potential mediating role of CSF LMO4 between Aβ pathology and tau pathology.

RESULT: LMO4 levels were decreased in participants with abnormal Aβ levels and cognitive impairment. Lower CSF LMO4 levels were associated with increased Aβ and tau pathology, brain atrophy, cognitive decline, and postmortem neuropathology. CSF LMO4 partially mediated the relationship between Aβ and tau pathology and demonstrated acceptable discriminative ability in distinguishing Aβ-positive from Aβ-negative participants and amyloid PET-confirmed AD from non-AD cases.

CONCLUSION: CSF LMO4 plays a crucial role in the pathogenesis and progression of AD and may represent a potential therapeutic target for AD treatment.},
}

Humans
Male
Female
*Biomarkers/cerebrospinal fluid
*Alzheimer Disease/cerebrospinal fluid/pathology/diagnostic imaging/diagnosis
Amyloid beta-Peptides/cerebrospinal fluid
tau Proteins/cerebrospinal fluid
Aged
*LIM Domain Proteins/cerebrospinal fluid
Positron-Emission Tomography
Cross-Sectional Studies
Brain/pathology
*Adaptor Proteins, Signal Transducing/cerebrospinal fluid
Cognitive Dysfunction/pathology/cerebrospinal fluid
Aged, 80 and over
Longitudinal Studies

@article {pmid41447699,
year = {2025},
author = {Bakker, A and Albert, MSS and Rosenzweig-Lipson, S and Mohs, R},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e100819},
doi = {10.1002/alz70856_100819},
pmid = {41447699},
issn = {1552-5279},
mesh = {Humans ; Male ; *Biomarkers/blood ; Female ; *Cognitive Dysfunction/drug therapy/diagnostic imaging ; Aged ; *Levetiracetam/therapeutic use ; *Alzheimer Disease/drug therapy/diagnostic imaging ; Positron-Emission Tomography ; Magnetic Resonance Imaging ; Hippocampus/drug effects/diagnostic imaging/pathology ; Disease Progression ; Double-Blind Method ; Amyloid beta-Peptides ; },
abstract = {BACKGROUND: Hippocampal hyperactivity is a pathological hallmark of Alzheimer's disease (AD) and a prognostic indicator for AD progression and clinical cognitive worsening in amnestic mild cognitive impairment (aMCI). Extensive data indicate that hippocampal overactivity reflecting an imbalance in inhibitory and excitatory activity is a driver of neurodegeneration and the spread of tau pathology. AGB101 is a proprietary extended-release formulation of low dose levetiracetam in the dose range previously demonstrated to normalize hippocampal activity and improve cognitive performance in aMCI. The HOPE4MCI clinical trial used a 78-week protocol of AGB101 treatment to assess progression in amyloid-positive patients with MCI due to AD.

METHODS: A total of 164 participants who were amyloid positive by PET imaging were randomized to placebo or AGB101 treatment using the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score as the primary outcome measure. MRI scans obtained in the study at baseline and after 78 weeks were analyzed providing volume measures of key structures of the medial temporal lobe relevant to AD progression. Blood samples collected at 78 weeks in the study were also analyzed for plasma biomarkers in those participants.

RESULT: In a pre-specified subgroup analysis, ApoE-4 carriers, showed no effect of treatment on any measure. However, in ApoE-4 non-carriers, AGB101 treated participants showed a 40% benefit on the CDR-SB score compared to placebo. These results were not significant due to the planned limited sample size. However, in the ApoE-4 non-carriers AGB101 treatment significantly reduced atrophy of the entorhinal cortex. That reduction in atrophy was significantly coupled with the change in CDR-SB and with NFL and GFAP plasma biomarkers of disease.

CONCLUSION: Extensive preclinical and clinical studies show that low dose levetiracetam normalizes aberrant network activity and restores inhibitory and excitatory network balance. The HOPE4MCI clinical trial shows that there is meaningful benefit on the CDR-SB over 18-month AGB101 treatment and a significant reduction in neurodegeneration in the non-carriers of ApoE-4 with MCI due to AD. These findings support the view that reducing hippocampal hyperactivity confers benefit and further testing of AGB101 in patients with MCI due to AD who are non-carriers of ApoE-4 is warranted.},
}

Humans
Male
*Biomarkers/blood
Female
*Cognitive Dysfunction/drug therapy/diagnostic imaging
Aged
*Levetiracetam/therapeutic use
*Alzheimer Disease/drug therapy/diagnostic imaging
Positron-Emission Tomography
Magnetic Resonance Imaging
Hippocampus/drug effects/diagnostic imaging/pathology
Disease Progression
Double-Blind Method
Amyloid beta-Peptides

@article {pmid41447693,
year = {2025},
author = {Bublitz, EF and Hulle, CAV and Zylstra, H and Cronin, K and Cole, A and Johnson, KM and Rivera-Rivera, LA and Beckman, E and Eierman, AC and Wilson, RE and Chappell, RJ and Asthana, S and Gleason, CE and Zetterberg, H and Johnson, SC and Carlsson, CM},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e101654},
doi = {10.1002/alz70856_101654},
pmid = {41447693},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; Male ; Aged ; Middle Aged ; Female ; Magnetic Resonance Imaging ; Veterans ; Double-Blind Method ; *Alzheimer Disease ; *Eicosapentaenoic Acid/analogs & derivatives/therapeutic use ; Apolipoproteins E/genetics ; *Brain/drug effects/diagnostic imaging/blood supply ; Cerebrovascular Circulation/drug effects ; Genotype ; },
abstract = {BACKGROUND: Veterans are more likely to develop vascular disease and Alzheimer's disease (AD) than non-veterans. Icosapent ethyl (IPE), a form of the omega-3 fatty acid eicosapentaenoic acid, reduces risk for major adverse cardiovascular events and lowers triglycerides. Improvement in vascular health may also reduce the risk of developing AD. 4D flow MRI, using PCVIPR (phase contrast vastly undersampled isotropic projection), offers direct study of blood flow and arterial stiffness in the brain. PCVIPR imaging may help uncover the effects of IPE on cerebrovascular health, and the relationship with APOE genotype and cerebrospinal fluid (CSF) biomarkers.

METHODS: The Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid (BRAVE-EPA) study enrolled VA-eligible, cognitively unimpaired Veterans, ages 50-75, at the Veteran's Hospital in Madison, Wisconsin. The study was a randomized, double-blind, placebo-controlled clinical trial of 4 g daily IPE (Vascepa®) treatment for 18 months. Participants had PCVIPR MRI, APOE genotyping and levels of CSF vascular health/inflammation biomarkers assayed with the NULISAseq CNS disease panel. PCVIPR imaging was completed on a 3T GE x750 scanner at baseline, month 9 and month 18. Image analysis was done with the Quantitative Velocity Tool in MATLAB. The PCVIPR measurements analyzed were mean blood flow (MF), pulsatility index (PI) and total cerebral blood flow (CBF; cervical internal carotid arteries + basilar artery). Interactions between variables were assessed with a Mann-Whitney U test and using correlation analysis.

RESULTS: IPE treatment for 18 months did not significantly change MF, PI, or CBF measures (IPE: n = 41, placebo: n = 44; MF p-value range: 0.064-0.93; PI p-value range: 0.061-0.94; CBF p-value: 0.33). APOE ε4 carriers (n = 28) and non-carriers (n = 89) had similar baseline blood flow (MF p-value range: 0.16-0.92; PI p-value range: 0.055-0.98). In the full sample (n = 123), baseline CSF levels of vascular biomarkers were significantly correlated with baseline PI (p-value range: <0.0001-0.99; Figure 2). In contrast, few CSF vascular biomarkers were significantly correlated with MF (p-value range: 0.032-0.96; Figure 1).

CONCLUSION: IPE treatment did not significantly impact PCVIPR measures of cerebral blood flow. Baseline vascular CSF biomarker levels, but not APOE ε4 carrier status, significantly correlated with baseline PCVIPR measures of PI and to a lesser extent MF.},
}

Humans
*Biomarkers/cerebrospinal fluid
Male
Aged
Middle Aged
Female
Magnetic Resonance Imaging
Veterans
Double-Blind Method
*Alzheimer Disease
*Eicosapentaenoic Acid/analogs & derivatives/therapeutic use
Apolipoproteins E/genetics
*Brain/drug effects/diagnostic imaging/blood supply
Cerebrovascular Circulation/drug effects
Genotype

@article {pmid41447680,
year = {2025},
author = {Ibanez, L},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e101336},
doi = {10.1002/alz70856_101336},
pmid = {41447680},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid ; *Alzheimer Disease/diagnosis/cerebrospinal fluid/diagnostic imaging ; tau Proteins/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Positron-Emission Tomography ; Brain/diagnostic imaging ; },
abstract = {BACKGROUND: At the beginning of the century, Alzheimer disease (AD) biomarkers were only used in research studies and included hippocampal volume and cerebrospinal fluid (CSF) concentrations of Aβ42, total tau, and tau phosphorylated at position 181 (p-tau181). Twenty-five years later, imaging and fluid biomarkers have become critical tools in AD clinical trials and are increasingly being used in clinical care.

METHODS: The development of imaging and fluid AD biomarkers will be reviewed. The evolving roles of different modalities of biomarkers in research, clinical trials, and clinical care will be described.

RESULTS: In 2004, the first radiotracer that bound amyloid plaques was reported, which enabled visualization of the amount and regional distribution of amyloid plaques in the brains of living individuals via positron emission tomography (PET). Radiotracers binding to insoluble tau aggregates were described in 2013 and 2014. The use of amyloid and tau PET as a reference standard, as well as improvements in fluid biomarker assay technology, led to the first of many accurate AD blood tests in 2017 and 2018. These imaging and fluid biomarkers of AD have undergone waves of development, validation, and regulatory approval. AD research studies now use biomarkers extensively to study the biology of disease. Clinical trials use biomarkers to confirm that participants have AD pathology and to monitor the effects of treatment. AD biomarkers are increasingly being used in the clinical diagnosis of AD. The high acceptability and accessibility of AD blood tests may enable AD biomarker testing to become the standard of care in patients with cognitive impairment. In the future, if trials of preventative treatments are positive, AD biomarker testing of cognitively unimpaired older individuals may become routine.

CONCLUSIONS: Advances in imaging and fluid biomarkers over the past quarter century have enabled greater understanding of AD biology and led to the successful development, approval, and clinical use of disease-modifying AD treatments that target amyloid pathology. The clinical availability of AD-specific treatments and high-accuracy AD blood tests is currently transforming the clinical diagnosis and care of patients with AD.},
}

Humans
*Biomarkers/cerebrospinal fluid
*Alzheimer Disease/diagnosis/cerebrospinal fluid/diagnostic imaging
tau Proteins/cerebrospinal fluid
Amyloid beta-Peptides/cerebrospinal fluid
Positron-Emission Tomography
Brain/diagnostic imaging

@article {pmid41447677,
year = {2025},
author = {Chen, X},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e101739},
doi = {10.1002/alz70856_101739},
pmid = {41447677},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; Female ; *Alzheimer Disease/drug therapy/blood ; Aged ; Amyloid beta-Peptides/blood ; tau Proteins/blood ; Neurofilament Proteins/blood ; Aged, 80 and over ; Glial Fibrillary Acidic Protein/blood ; Mental Status and Dementia Tests ; Neuropsychological Tests ; Peptide Fragments/blood ; Middle Aged ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, posing significant global health and societal challenges. Lecanemab is a disease-modifying therapy approved for mild AD. In this report, we present real-world data on the efficacy and safety of lecanemab, and explore the role of AD-related serum biomarkers in monitoring treatment efficacy in a real-world setting.

METHOD: Cognitive function was assessed using AD assessment scale-cognition (ADAS-Cog), clinical dementia rating scale-sum of boxes (CDR-SB), montreal cognitive assessment (MoCA), mini-mental state examination (MMSE), and frontal assessment battery (FAB) at baseline and every follow-up. Serum biomarkers, including neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), Aβ 1-40, Aβ 1-42, p-tau 181, and p-tau 217, were monitored with chemiluminescence assay at all time points.

RESULT: Fifty-one AD patients meeting ATN criteria were enrolled (CDR 0.5: n = 25; CDR 1: n = 14; CDR 2: n = 12). Significant improvements were observed in ADAS-Cog (+4.36 points, p <0.001), CDR-SB (+0.31 points, p = 0.010), and MoCA (+1.40 points, p = 0.002) at 7 months, with no significant change in MMSE. Only serum p-tau 181 decreased significantly (p = 0.031), while p-tau 217 showed a non-significant trend. Spearman correlation analysis revealed associations between serum p-tau181, p-tau217, and cognitive scores. The adjusted linear mixed-effects model indicated a significant association between serum p-tau 181 and ADAS-Cog scores (β=0.3546, p <0.001). No serious adverse events occurred. Infusion reactions were reported in 7.69% of patients, and 9.62% discontinued due to asymptomatic amyloid-related imaging abnormalities (ARIA).

CONCLUSION: In the real world, lecanemab may be safe and effective in the treatment of mild-to-moderate AD, and dynamic monitoring of serum p-tau 181 may be helpful to observe the efficacy during treatment. AD patients with severe cognitive impairment and significant white matter lesions should be closely monitored for adverse reactions, such as ARIA.},
}

Humans
*Biomarkers/blood
Male
Female
*Alzheimer Disease/drug therapy/blood
Aged
Amyloid beta-Peptides/blood
tau Proteins/blood
Neurofilament Proteins/blood
Aged, 80 and over
Glial Fibrillary Acidic Protein/blood
Mental Status and Dementia Tests
Neuropsychological Tests
Peptide Fragments/blood
Middle Aged

@article {pmid41447672,
year = {2025},
author = {Coughlan, GT},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e101667},
doi = {10.1002/alz70856_101667},
pmid = {41447672},
issn = {1552-5279},
mesh = {Humans ; Female ; Male ; *tau Proteins/blood ; Positron-Emission Tomography ; Aged ; *Amyloid beta-Peptides/blood ; *Biomarkers/blood ; *Alzheimer Disease/diagnostic imaging/blood ; Longitudinal Studies ; Brain/diagnostic imaging/metabolism ; Phosphorylation ; Peptide Fragments/blood ; Aged, 80 and over ; Middle Aged ; },
abstract = {BACKGROUND: Data suggest that women exhibit elevated insoluble tau aggregates relative to age-matched men. Whether this sex difference is due to upstream soluble phosphorylated tau(p-tau) is unclear. We examined whether sex and amyloid-β(Aβ) predict baseline plasma p-tau217 and whether baseline plasma p-tau217 and p-tau217/Aβ42 predict longitudinal tau positron emission tomography(PET) in a sex-specific manner.

METHOD: 998 clinically normal individuals (mean-age:71; 429 APOEε4 carriers; 525 Aβ+; Table) from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease trial, the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration study(A4/LEARN), the Wisconsin Registry for Alzheimer's Prevention(WRAP), Harvard Aging Brain Study(HABS) and Alzheimer's Disease Neuroimaging Initiative(ADNI) had multiple tau-PET scans and at least one measurement of ptau217. Average tau-PET follow-up time was 3.6 years (range=1.3-8.9years. We used regression models of soluble p-tau217 to examine cross-sectional sex×Aβ interaction. Longitudinally, random-effects models (participant-specific intercepts and slopes) estimated the sex×baseline-p-tau217 time interaction on each of nine apriori tau-PET regions (including rostral middle frontal gyri, fusiform gyrus, inferior temporal and parietal gyri, the superior parietal lobule, precuneus, lateral occipital cortex, parahippocampal and amygdala). All models adjusted age. ADNI used the p-tau217/Aβ42 ratio.

RESULT: In A4/LEARN, women exhibited elevated baseline p-tau217 concentrations relative to men, particularly at higher neocortical-Aβ(β=-0.16, p = 0.008). No significant interactions were observed in the other cohorts. Longitudinal sex×baseline-p-tau217×time interactions were significant in five, six, four, and seven tau-PET regions in A4/LEARN, WRAP, HABS and ADNI cohorts, respectively. Across all significant interactions, women showed worse tau trajectories than men at higher p-tau217(A4/LEARN, WRAP, HABS; Figure 1) and p-tau217/Aβ42(ADNI; Figure 2) concentrations. Covarying for APOEε4-status, baseline Aβ and baseline-tau-SUVR did not attenuate the longitudinal sex effects.

CONCLUSION: These findings suggest that sex differences in tau proliferation may be exacerbated by upstream soluble p-tau levels. Earlier therapeutic approaches reducing soluble p-tau levels might be particularly important in women.},
}

Humans
Female
Male
*tau Proteins/blood
Positron-Emission Tomography
Aged
*Amyloid beta-Peptides/blood
*Biomarkers/blood
*Alzheimer Disease/diagnostic imaging/blood
Longitudinal Studies
Brain/diagnostic imaging/metabolism
Phosphorylation
Peptide Fragments/blood
Aged, 80 and over
Middle Aged